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Control of kidney development by calcium ions
Biochimie 93 (2011) 2126e2131
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Biochimie journal homepage: www.elsevier.com/locate/biochi
Mini-review
Control of kidney development by calcium ions Thierry Gilbert*, Catherine Leclerc, Marc Moreau Centre de Biologie du Développement, Université de Toulouse, CNRS UMR 5547, Toulouse, France1
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 April 2011 Accepted 8 July 2011 Available online 23 July 2011
From the formation of a simple kidney in amphibian larvae, the pronephros, to the formation of the more complex mammalian kidney, the metanephros, calcium is present through numerous steps of tubulogenesis and nephron induction. Several calcium-binding proteins such as regucalcin/SMP-30 and calbindin-D28k are commonly used to label pronephric tubules and metanephric ureteral epithelium, respectively. However, the involvement of calcium and calcium signalling at various stages of renal organogenesis was not clearly delineated. In recent years, several studies have pinpointed an unsuspected role of calcium in determination of the pronephric territory and for conversion of metanephric mesenchyme into nephrons. Influx of calcium and calcium transients have been recorded in the pool of renal progenitors to allow tubule formation, highlighting the occurrence of calcium-dependent signalling events during early kidney development. Characterization of nuclear calcium signalling is emerging. Implication of the non-canonical calcium/NFAT Wnt signalling pathway as an essential mechanism to promote nephrogenesis has recently been demonstrated. This review examines the current knowledge of the impact of calcium ions during embryonic development of the kidney. It focuses on Ca2þ binding proteins and Ca2þ sensors that are involved in renal organogenesis and briefly examines the link between calcium-dependent signals and polycystins. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: Calcium Nephron NFAT Calbindin Pronephros Metanephros
1. Kidney development: an overview Renal organogenesis founds its origin within the intermediate mesoderm, a territory located between the somitic mesoderm and the lateral plate mesoderm. In amniotes (birds, mammals, reptiles) the formation of the kidney progresses through three developmental stages, the pro-, meso- and meta-nephros, and the first two stages resolve with the formation of the following stage (for review see Saxén [1]) (Fig. 1A). These three successive renal structures develop in an anterior to posterior direction. They represent organs of increasing complexity and they all contain a similar basic unit of filtration: the nephron. Schematically, all nephrons are based upon a common architecture that encompasses a vascular pole to filter blood, a tubule to reabsorb and secrete solutes, and a collecting duct to drain waste for excretion. Although the first kidney to form, the pronephros, is vestigial and rudimentary in higher vertebrates, it is fully functional in fish embryos and amphibian larvae. In the frog Xenopus laevis, each pronephros consists of a single nephron,
* Corresponding author. Centre de Biologie du Développement, Université Paul Sabatier de Toulouse, Bat 4R3, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France. Tel.: þ33 561 558 695; fax: þ33 561 556 507. E-mail address: [email protected] (T. Gilbert). 1 GDR 2688 “Role of calcium in gene expression in normal and pathological conditions”. 0300-9084/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biochi.2011.07.007
consisting of a large glomus that filters into the coelom and a tubule whose proximal part collects the filtrate via three ciliated nephrostomes, while the distal part is connected to the cloaca [2]. This unique nephron was originally thought to be very simple, but the organization of the pronephric tubule was recently shown to share the same tubular segmentation than a typical mammalian nephron [3]. Following the caudal extension of the pronephric tubule, the nephric duct arises and this structure is fully required to generate the next kidney, the mesonephros. The mesonephros consists of a successive array of epithelial tubules induced by the nephric duct among the adjacent nephrogenic mesenchyme. Each mesonephron consists of a capillary tuft called the glomerulus that filters blood from the dorsal aorta into a small cavity delineated by the Bowman’s capsule. This primary filtrate is then poured directly into a mesonephric tubule that connects to the nephric duct. In amphibian and fishes, the mesonephros is the permanent kidney and it may contain more than one hundred units of filtrations. Interestingly, this number is variable since regenerative capacity exists in the mesonephros, either to adapt to growth and increased need of filtration or to face chemical insult and damaged renal function [4,5]. In higher vertebrates only the mesonephrons induced first, i.e. those that lay in an anterior position, display convoluted tubules and are connected to the nephric duct (Fig. 1A). The tubules lying in a more posterior position within the nephrogenic chord never fused with the nephric duct [6]. As the nephric
T. Gilbert et al. / Biochimie 93 (2011) 2126e2131
Fig. 1. Overview of renal organogenesis in vertebrates. A. Three successive embryonic kidneys appear throughout renal organogenesis. Pronephros and mesonephros are functional kidneys of the larval and adult amphibian, respectively. In mammals, the pronephros is vestigial, the mesonephros is the embryonic form of the kidney and the metanephros will form the definitive kidney. Formation and extension of the nephric duct along the nephrogenic chord dictate the appearance of the successive kidneys. The mesonephric tubules located in a more rostral position are connected to the nephric duct, as opposed to the second set of mesonephric tubules that are in a more caudal position. The ureteric bud outgrowth interacts with the metanephric mesenchyme and initiates metanephros formation, characterized by active UB branching morphogenesis and exponential nephron induction. The mesonephros will then start to degenerate. The vascular pole in each type of kidney is represented by a red dot. B. Whole mount in situ hybridization of SMP-30 in late tadpole stage Xenopus laevis embryo. On this lateral view the expression of SMP-30 is clearly restricted to the pronephros, with a very strong labelling of the pronephric tubules and a faint signal present in the nephric duct. Inset shows the prominent staining in the proximal tubules. C. Whole mount immuno-detection of Calb1 protein in embryonic day 13.0 mouse metanephros. Staining is present in the entire ureteric bud epithelium, from its most distal part to every tip. MM, metanephric mesenchyme; MT, mesonephric tubule; NC, nephrogenic chord; ND, nephric duct; UB, ureteric bud; Bars represent 1 mm and 0.1 mm in B and C, respectively.
duct and the nephrogenic chord continue to extend, the cranial mesonephrons start to degenerate. Then the metanephros or final kidney arises when an outgrowth of the nephric duct named the ureteric bud interacts with the caudal end of the nephrogenic chord. Signals between the epithelial bud and the metanephric mesenchyme lead to an active branching morphogenesis of the former and condensation of the latter around the extremities of the dividing ureteric bud. This condense mesenchyme differentiates into a renal corpuscule, comprising a glomerular and a tubular segment that will differentiate into a nephron that connects to the growing ureteric bud. Several thousands of nephrons will then be generated. The arborisation of the ureteric bud can therefore be viewed as an effective way for multiplying the sites of nephron induction within the metanephrogenic mesenchyme. However, as opposed to the mesonephros, no formation of new nephron can occurred in mammals when nephrogenesis is completed. According to mammalian species, nephron endowment is acquired in
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utero or a few days postnatally, and plasticity of nephron number is the rule in every species [7]. Taking advantages of the experimental accessibility of frog and chick embryos and of genetically modified murine models, it became apparent that the molecular mechanisms involved in development and patterning of the pronephros, mesonephros and metanephros are remarkably conserved within vertebrates. The specification of the pronephric territory is the key event that delineates all successive steps of renal organogenesis. It occurs very early in amphibian, at the end of gastrulation, and the first morphological changes are observed by mid-neurula within the prospective pronephric area in the vicinity of the fifth to sixth somite. In the mouse, at embryonic day 8.5 (E8.5), the pronephros is barely detectable and levels with presumptive somites 5e8. Similar inductive events, signalling cascades and gene products have been shown to drive pronephric to metanephric differentiation [8,9]. The early expression of several transcription factor families, such as Osr, lhx and Pax, characterizes the pronephros field [10,11]. Delineation of its identity and definition of its size are dependent on the Irx family of homeogenes [12] while expression of the transcriptional repressor Tbx2 has just been proposed to control the boundary of the pronephric territory [13]. Specification of the nephric lineage is then dependent upon Pax genes [14]. The formation of the nephric duct primordium that extends caudally is the critical event for the formation of both meso- and meta-nephros. If little is known on the molecular strengths and signals that contribute to the elongation of the nephric duct, the specification of the intermediate mesenchyme towards a mesonephric or metanephric phenotype is largely dependent upon its antero-posterior patterning by Hox11 genes. As shown by Mugford and colleagues, the homeogene Hoxd11 activates the Six2 transcription factor that is required for the acquisition and maintenance of metanephric progenitors [15]. In conjunction with Eya genes family, the gene network Pax/Six/Eya specifies the metanephric lineage. For a more detailed update on early renal cell fate determination, the reader can refer to [16]. 2. Calcium signalling is present throughout kidney development Calcium (Ca2þ) is an intracellular messenger involved in a variety of signalling processes, from signal transduction to transcription, from cell division to apoptosis, from differentiation to oncogenesis. The wealth of events in normal function and disease controlled by calcium is overwhelming [17]. Recent studies based upon Ca2þ imaging in various animal species have demonstrated that Ca2þ signals are associated with many of the sequential steps and processes that are common to animal development. During early vertebrate development, Ca2þ pulses, waves and gradients have been recorded. It is now acknowledged that they are involved in coordination of cell movements, axis specification and the development of the nervous system, heart and muscle (for review see [18,19]). Regarding kidney development, it must be acknowledged that calcium signalling has been largely ignored although specific labelling of embryonic kidneys by calcium-binding proteins was one of the most commonly used methods to assess pronephros and metanephros development (Fig. 1). In frog larvae, the senescence marker protein-30 (SMP-30), also named regucalcin, is a highly conserved Ca2þ binding protein and is selectively expressed in pronephric tubules [20]. It labels strongly the proximal tubules and to a lesser extent the intermediate segment (Fig. 1B). Its expression in cortical collecting duct of E15 mouse kidney has also been reported from microarray expression profiles [21]. In murine development, renal expression of calbindin-D28k (calb1) is a standard marker for ureteric bud and embryonic collecting duct (Fig. 1C). Calb1 expression starts in cells of the
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mesonephric duct at E11 in the mouse and E13 in the rabbit, and is then observed in the metanephric duct [22,23]. High levels of Calb1 were also found in the developing chick kidney, in mesonephric distal and connecting tubules, and subsequently in the Wolffian duct [24]. Data highly suggest that the expression of Calb1 overlaps with the formation of the mesonephros, i.e. when the nephric duct induces among nephrogenic cells a mesenchyme to epithelium transition. To this respect, the appearance of Calb1 expression at the most posterior end of the connecting tubule in the pronephros is revealing [3]. And it is noteworthy that the high expression of Calb1 at site of nephron formation stops upon cessation of nephrogenesis to become restricted to the distal tubule [25]. Beside these two well characterized renal markers, two additional calbindins are expressed in the developing kidneys (Table 1). Calretinin or calb2 is expressed in mesonephric tubules [24] and calbindin-D9k also called calb3 is expressed later in the metanephric kidney in convoluted distal tubules [15,22]. Calbindin 1 and 2 belong to a subset of cytosolic proteins of the EF-hand family and both display the typical helix-Ca2þ binding loop-helix structure. Calb3 on the other hand is a member of the large S100 family. All three calbindins are considered as true Ca2þ buffers as well as the first isolated Ca2þ binding protein of the EF-hand family, parvalbumin [26]. This latter has barely been studied during kidney development. One report mentions its expression within collecting duct and distal tubules of human embryonic metanephros [27]. None of the transgenic mouse strains with altered calbindin(s) or parvalbumin expression display a distinguishable renal phenotype, likely due to compensatory molecular regulation of Ca2þ homeostasis. However, the use of parvalbumin as a strong diagnostic marker for renal neoplasms, specifically chromophobe renal cell carcinoma, is suggestive of an altered calcium signalling in those collecting duct-derived tumours that show no expression of calb1 and 2 [27]. The role of parvalbumin during early kidney development cannot be fully excluded since abundant parvalbuminimmunoreactive materials in proximal tubules along the frog kidney have been reported [28]. Most of the Ca2þ binding proteins are rather classified as Ca2þ sensors. The prototypical example calmodulin does not exhibit specific expression domains throughout renal organogenesis, consistent with its role as a ubiquitous Ca2þ sensor. Calreticulin or calregulin, is another good example of an expression very early during kidney organogenesis as reported in fish pronephros [29]. Upon conversion of the metanephric mesenchyme into nephron,
calretinin expression is significantly enhanced in newly formed epithelial structures [30]. As reported in Table 1, additional S100 and proteins containing EF-hand Ca2þ binding domain (S100A5, S100B, Efcab1 and Gca) are expressed in the developing murine nephric duct at E10.5 and in the ureteric bud and derivatives [21]. Among these proteins, S100B can interact with the tumour suppressor p53 to regulate its tetramerization and transcriptional activity in a Ca2þ dependent manner [31,32]. Since p53 is a known regulator of metanephric development [33] one may propose that Ca2þ-bound S100B contributes to metanephros formation. Among the annexin family that are Ca2þ dependent phospholipid binding proteins, the annexin IV turned out to play an important role in pronephros morphogenesis [34]. Absence of annexin IV at the luminal pronephric tubule surface lead to enlarged pronephric tubule, indicating that annexin IV is involved in regulation of passive membrane permeability to water and protons, as suggested in vitro [35]. Another member of the annexin family, annexin 11 (anxa11), is selectively present in the ureteric bud and collecting duct within E15.5 mouse kidney. This restricted expression profile brings a supplementary clue for the likely participation of anxa11 to Ca2þ homeostasis via membrane traffic and/or regulation of ion channels activities events in the developing metanephros [36]. 2.1. Calcium, a necessary signal for renal progenitors In Xenopus embryo, the presumptive pronephros territory at early tailbud stage can be specifically labelled by NDRG1, a member of the N-myc downstream-regulated gene family. The depletion of xNDRG1 causes failure of pronephros development [37]. One of the signals that modulate NDRG1 expression is an intracellular rise in Ca2þ [38]. This prompts us to study the intracellular Ca2þ dynamics in Xenopus embryos and analyze their effects on pronephros formation. Using the bioluminescent Ca2þ sensitive photoprotein aequorin combined with photon imaging microscope, our group has recently demonstrated that Ca2þ is a necessary signal to trigger pronephric tubule differentiation [39]. First we showed that in intact embryo, Ca2þ transients peak shortly after completion of gastrulation and gradually decrease. Several successive waves of Ca2þ are observed in the pronephric territory at each steps of pronephros formation, from gastrula to early tailbud stage, when the pronephros anlage emerges from the intermediate mesoderm. Second, by injecting an inactive caged Ca2þ chelator diazo-2 in the lateral marginal zone of 4-cell stage embryo with EGFP mRNA as
Table 1 Expression of Ca2þ buffers and Ca2þ sensors during renal organogenesis. Common names
Gene symbol
Pronephrosa
Mesonephrosa
Metanephrosa
References
Regucalcin, SMP-30 Calbindin-D28k Calretinin Calbindin-D9k, Calb3, S100g Parvalbumin
Rgn Calb1 Calb2/CR Calb3/S100g Pvalb
PT (Xl) CT (Oc) nd nd PT (Xl)
nd MT, ND (Gg, Oc) MT, CT (Gg) nd nd
cCD, UT UB, CD, DT PT (Gg) DT CD, DT (Hs)
[20,21] [22e24] [24] [15,22] [27,28]
Calreticulin, calregulin S100 Ca2þ binding protein A5 S100 Ca2þ binding protein B EF-hand Ca2þ binding domain 1 Grancalcin Annexin A4 Annexin A11 Calcineurin A
Calr S100a5 S100b Efcab1 Gca Anxa4 Anxa11 Ppp3ca
þþ (Om) nd nd nd nd PT nd nd
nd nd nd ND E10.5 nd nd nd nd
RC, PT, DT (Rn) mCD UB E10.5 UB E10.5 UT, cCD, RI nd UB, cCD, mCD CM, RI
[29,30] [21] [21] [21] [21] [34] [21] [21,52]
cCD, cortical collecting duct; CD, collecting duct; CT, connecting tubule; mCD, medullary collecting tubule; CM, cap mesenchyme; DT, distal tubule; PT, proximal tubule; MT, mesonephric tubule; ND, nephric duct; RC, renal corpuscule; RI, renal interstitium; UB, ureteric bud; UT, ureteric tip. þþ: highly expressed. nd: not documented. Gg, Gallus gallus; Hs, Homo sapiens; Oc, Oryctogalus cuniculus; Om, Oncorhynchus mykiss; Rn, Rattus norvegicus; Xl, Xenopus laevis. a Data are limited to E15.5 murine metanephros unless other specification.
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tracer, we demonstrated that uncaging diazo-2 in the pronephric domain, prior to the first sign of pronephric differentiation produced embryos with a shortened and widened pronephric tubule. An increase in intracellular calcium is therefore required to allow optimal tubule differentiation in the amphibian kidney. The question then arises if a similar evolutionary conserved mechanism occurs in the metanephros of higher vertebrates. N-myc is highly expressed in the induced metanephric mesenchyme, and is a feature of early differentiation since its expression decreases dramatically during differentiation [40]. N-myc is an important regulator of rapid cell proliferation in the cap mesenchyme. Reduction in N-myc protein levels lead to renal hypoplasia secondary to a decrease in cell proliferation [41] whereas enhanced expression was commonly observed in nephroblastoma or Wilms’ tumours [42]. Very few publications are available on NDRG family members in metanephros development. In situ hybridisation data from the GUDMAP renal expression database show that Ndrg1 is expressed in the metanephric mesenchyme and early tubule when Ndrg2 is restricted to the cap mesenchyme [21]. In clear cell renal cell carcinoma NDRG2 expression is significantly lower than in normal renal tissues, consistent with its proposed role of a tumour suppressor [43]. It is therefore tempting to propose that N-myc downstream-regulated gene expression in embryonic mouse kidney may occur in conjunction with an intracellular rise of Ca2þ in vivo. To this regard, the recent recording of repetitive calcium waves in metanephric blastema cells of explanted embryonic rat kidney [44] provides a significant breakthrough towards a more consensual requirement of Ca2þ for kidney development, from amphibian to mammalian kidney. This current proposal is even reinforced by the report of cultured human foetal kidney epithelial progenitor cells that maintain a mesenchymal phenotype under low calcium-containing medium [45]. The increase of intracellular calcium in the pool of nephron progenitors following induction brings us to the next question: what are the targets of this signal?
(CnABP), expressed in mesenchymal progenitor cells at the onset of metanephric kidney development was shown to be overexpressed in Wilms’ tumours [53]. The interaction between CnABP and calcineurin A leads to an inhibition of the phosphatase activity and defective NFAT-mediated signalling. During embryonic kidney development, the canonical Wnt/ b-catenin signalling is the major pathway regulating the early step of nephron induction i.e. formation of mesenchymal aggregates [54]. However, the failure to fully rescue the tubulogenesis defects observed in Wnt4 and Wnt9b null mice following overexpression of b-catenin [54] suggests that activation of canonical Wnt signalling can inhibit non-canonical Wnt responses [55]. The current idea is that tubulogenesis per se requires an attenuation of b-catenin signalling [56], consistent with the reduced pronephric tubulogenesis observed upon excess of b-catenin [57]. Among the non-canonical Wnt signalling pathways, the calcineurin/NFAT pathway turned out to be crucial for nephrogenesis with NFATc proteins transducing the Ca2þ signals to the nucleus. The experimental proofs and molecular characterization of calcium-mediated nephrogenesis were brought earlier this year by the groups of A. Perantoni and of P. Hohenstein. The first demonstrated that tubulogenesis in metanephric mesenchyme occurs by a non-canonical Wnt/calcium-dependent mechanism [58]. Wnt4-treated primary metanephric mesenchymal cells exhibited a significant Ca2þ influx leading to tubule formation that was blocked in presence of Ca2þ chelator. The second found that calcium/NFAT pathway functions downstream of Wnt4 in nephrogenesis [59]. Among the NFAT genes, Nfatc3 and Nfatc4 were abundantly expressed in the metanephric mesenchyme. Altogether, these data demonstrated that Ca2þ influx and NFAT signalling not only promote nephrogenesis but that they are also required for complete mesenchymal to epithelial transition during nephron formation.
2.2. Calcineurin/NFAT signalling controls nephron formation
One last example of the involvement of calcium signalling during kidney development is illustrated by the link between calcium-dependent signals and polycystins. Polycystin-1 (PC-1) and -2 (PC-2) are the products of the genes PKD1 and PKD2 that are mutated in many cases of autosomal dominant polycystic kidney disease (ADPKD), characterized by the progressive development of fluid-filled cysts from the tubules and collecting ducts of injured kidneys [60]. PC-1 is a highly glycosylated trans-membrane protein expressed in developing tubular epithelia and distal branches of the ureteric bud [61]. PC-2 is detected earlier, in the mesonephros, before being highly expressed in the ureteric bud and metanephric mesenchyme of the developing human metanephros [62]. Then PC-2 expression became prominent in maturing proximal and distal tubules [63]. Both proteins belong to the transient receptor potential (TRP) superfamily, and are also named TRPP1 and 2. TRPs are cation channels involved in many physiological processes along the nephron (for review see [64,65]). In fact, TRPP1 is not a true cation permeable channel and displays very limited sequence similarity with TRPs. Its classification within the TRPP subfamily is based upon the presence of six membrane-spanning regions at the C-terminus that resemble the PC-2 structure. PC-1 and PC-2 require intact carboxyl termini and the coiled-coil domain to interact with each other. Nevertheless, both polycystins are essential for the establishment and maintenance of epithelial tubular structures in the kidney [66]. Co-assembly of these two polycystin proteins produces new calcium-permeable non selective cation currents, and this channel activity is lost in ADPKD [67]. The PC-1/PC-2 complex localized to the primary cilia functions as a mechanosensitive receptor allowing Ca2þ entry into the cell [68]. In this complex, PC-1 is currently viewed as a polymodal receptor that
Clues about the unsuspected role of calcium-mediated mechanisms in metanephric nephron formation came first from studies investigating the potential toxicity of cyclosporin A (CsA) during kidney development. CsA is a potent immuno-suppressive drug that interacts with calcineurin, a protein phosphatase that is activated upon calcium/calmodulin binding. This interaction prevents the dephosphorylation of cytosolic NFAT (Nuclear Factor of Activated T cells) and its nuclear translocation, leading to transcriptional modifications of genes expressions (for review see [46]). The original observation of a link between calcium and nephrogenesis was made on rat metanephros organ culture. We showed that the presence of the calcineurin inhibitor CsA in the culture medium was deleterious to in vitro nephron induction in a dose-dependent manner [47]. Because an unaltered branching pattern of the ureteric bud was observed, the nephron deficit was likely to result from an impaired capacity of the mesenchyme to convert into epithelium [48]. These data were validated in vivo in a rabbit model of in utero exposure to CsA. Upon CsA administration simultaneous to the onset of renal organogenesis, a permanent nephron deficit was obtained in every pup [49]. Long term follow-up indicated a progressive chronic renal insufficiency in adulthood and systemic hypertension [50]. Additional calcineurin inhibitors have been shown to affect the development of pronephric tubules in Xenopus [51]. Therefore it became apparent that calcineurin-dependent pathway was involved in the developing kidney. This was confirmed in knockout mice for calcineurin A that display an absence of proliferation and a defective maturation of the nephrogenic zone [52]. More recently, a calcineurin A-binding protein
2.3. Calcium signal and polycystins
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controls the channel activity of PC-2 [69]. Other cellular locations have been reported for each polycystin, notably the basolateral plasma membrane for PC-1 and the endoplasmic reticulum for PC-2. This indicates that cilia-mediated mechanosensory stimuli are not the only mechanism implicating polycystin, but few investigations have addressed this issue. Additional Ca2þ channel proteins can also associate with PC-2, namely TRPC1 and TRPV4, to form polymodal sensory channel or hetero-complexes [70,71]. The strong expression pattern of TRPC1 in the embryonic proximal tubules and the restricted expression of TRPV4 to the ureteric bud tip epithelium suggest that a similar association with PC-2 may occur during kidney development [21]. One of the triggering events in regulating cellular Ca2þ homeostasis via intracellular Ca2þ pools seems to be the direct interaction of PC-2 with the type I inositol 1,4,5-triphosphate receptor [72]. Polycystin-2 downstream signalling pathway involves activation of intracellular Ca2þ release channels, especially the ryanodine receptor [73]. Attention has been focused on calcium in ADPKD because it is the most proximate signal to the PC-1/PC-2 complex. However, the role of Ca2þ signalling in the molecular mechanisms of cystogenesis in PKD is far from being understood. The ability of PC-1, independently of PC-2, to activate the calcineurin/NFAT signalling pathway via activation of the phospholipase C [74], further indicates that defects in Ca2þ transients leading to abnormal kidney development and cyst formation may occur via multiple signalling cascades. 3. Conclusions Increasing lines of evidence have highlighted calcium as a necessary signal for conversion of the pronephric and metanephric mesenchyme into a functional nephron epithelium. The triggering of the initial renal territory depends on calcium transients and the requirement upon calcium for mesenchyme to epithelium transition is now clearly demonstrated. Throughout renal organogenesis intracellular Ca2þ must therefore be tightly regulated. The presence of SMP-30 and Calbindin-D28k involved mostly in the efflux of Ca2þ across the plasma membrane confirms the need for a balanced calcium environment. Future research directions will be aimed at identifying members of the calcium homeostasome that participate in kidney development, and at determining the precise downstream targets of calcium-dependent signalling. New crosstalks between calcium and other signalling pathways will certainly be unveiled. References [1] L. Saxén, Organogenesis of the Kidney, vol. 19, Cambridge University Press, Cambridge, 1987. [2] P.D. Vize, E.A. Jones, R. Pfister, Development of the Xenopus pronephric system, Dev. Biol. 171 (1995) 531e540. [3] D. Raciti, L. Reggiani, L. Geffers, Q. Jiang, F. Bacchion, A.E. Subrizi, D. Clements, C. Tindal, D.R. Davidson, B. Kaissling, A.W. Brändli, Organization of the pronephric kidney revealed by large-scale gene expression mapping, Genome Biol. 9 (2008) R84. [4] N. Watanabe, M. Kato, N. Suzuki, C. Inoue, S. Fedorova, H. Hashimoto, S. Maruyama, S. Matsuo, Y. Wakamatsu, Kidney regeneration through nephron neogenesis in medaka, Dev. Growth Differ. 51 (2009) 135e143. [5] W. Zhou, R.C. Boucher, F. Bollig, C. Englert, F. Hildebrandt, Characterization of mesonephric development and regeneration using transgenic zebrafish, Am. J. Physiol. Renal Physiol. 299 (2010) F1040eF1047. [6] K. Sainio, P. Hellstedt, J.A. Kreidberg, L. Saxén, H. Sariola, Differential regulation of two sets of mesonephric tubules by WT-1, Development 124 (1997) 1293e1299. [7] C. Merlet-Benichou, T. Gilbert, J. Vilar, E. Moreau, N. Freund, M. LelievrePegorier, Nephron number: variability is the rule e causes and consequences, Lab. Invest. 79 (1999) 515e527. [8] A.W. Brändli, Towards a molecular anatomy of the Xenopus pronephric kidney, Int. J. Dev. Biol. 43 (1999) 381e395. [9] G.R. Dressler, The cellular basis of kidney development, Annu. Rev. Cell Dev. Biol. 22 (2006) 509e529.
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Biochimie journal homepage: www.elsevier.com/locate/biochi
Mini-review
Control of kidney development by calcium ions Thierry Gilbert*, Catherine Leclerc, Marc Moreau Centre de Biologie du Développement, Université de Toulouse, CNRS UMR 5547, Toulouse, France1
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 April 2011 Accepted 8 July 2011 Available online 23 July 2011
From the formation of a simple kidney in amphibian larvae, the pronephros, to the formation of the more complex mammalian kidney, the metanephros, calcium is present through numerous steps of tubulogenesis and nephron induction. Several calcium-binding proteins such as regucalcin/SMP-30 and calbindin-D28k are commonly used to label pronephric tubules and metanephric ureteral epithelium, respectively. However, the involvement of calcium and calcium signalling at various stages of renal organogenesis was not clearly delineated. In recent years, several studies have pinpointed an unsuspected role of calcium in determination of the pronephric territory and for conversion of metanephric mesenchyme into nephrons. Influx of calcium and calcium transients have been recorded in the pool of renal progenitors to allow tubule formation, highlighting the occurrence of calcium-dependent signalling events during early kidney development. Characterization of nuclear calcium signalling is emerging. Implication of the non-canonical calcium/NFAT Wnt signalling pathway as an essential mechanism to promote nephrogenesis has recently been demonstrated. This review examines the current knowledge of the impact of calcium ions during embryonic development of the kidney. It focuses on Ca2þ binding proteins and Ca2þ sensors that are involved in renal organogenesis and briefly examines the link between calcium-dependent signals and polycystins. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: Calcium Nephron NFAT Calbindin Pronephros Metanephros
1. Kidney development: an overview Renal organogenesis founds its origin within the intermediate mesoderm, a territory located between the somitic mesoderm and the lateral plate mesoderm. In amniotes (birds, mammals, reptiles) the formation of the kidney progresses through three developmental stages, the pro-, meso- and meta-nephros, and the first two stages resolve with the formation of the following stage (for review see Saxén [1]) (Fig. 1A). These three successive renal structures develop in an anterior to posterior direction. They represent organs of increasing complexity and they all contain a similar basic unit of filtration: the nephron. Schematically, all nephrons are based upon a common architecture that encompasses a vascular pole to filter blood, a tubule to reabsorb and secrete solutes, and a collecting duct to drain waste for excretion. Although the first kidney to form, the pronephros, is vestigial and rudimentary in higher vertebrates, it is fully functional in fish embryos and amphibian larvae. In the frog Xenopus laevis, each pronephros consists of a single nephron,
* Corresponding author. Centre de Biologie du Développement, Université Paul Sabatier de Toulouse, Bat 4R3, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France. Tel.: þ33 561 558 695; fax: þ33 561 556 507. E-mail address: [email protected] (T. Gilbert). 1 GDR 2688 “Role of calcium in gene expression in normal and pathological conditions”. 0300-9084/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biochi.2011.07.007
consisting of a large glomus that filters into the coelom and a tubule whose proximal part collects the filtrate via three ciliated nephrostomes, while the distal part is connected to the cloaca [2]. This unique nephron was originally thought to be very simple, but the organization of the pronephric tubule was recently shown to share the same tubular segmentation than a typical mammalian nephron [3]. Following the caudal extension of the pronephric tubule, the nephric duct arises and this structure is fully required to generate the next kidney, the mesonephros. The mesonephros consists of a successive array of epithelial tubules induced by the nephric duct among the adjacent nephrogenic mesenchyme. Each mesonephron consists of a capillary tuft called the glomerulus that filters blood from the dorsal aorta into a small cavity delineated by the Bowman’s capsule. This primary filtrate is then poured directly into a mesonephric tubule that connects to the nephric duct. In amphibian and fishes, the mesonephros is the permanent kidney and it may contain more than one hundred units of filtrations. Interestingly, this number is variable since regenerative capacity exists in the mesonephros, either to adapt to growth and increased need of filtration or to face chemical insult and damaged renal function [4,5]. In higher vertebrates only the mesonephrons induced first, i.e. those that lay in an anterior position, display convoluted tubules and are connected to the nephric duct (Fig. 1A). The tubules lying in a more posterior position within the nephrogenic chord never fused with the nephric duct [6]. As the nephric
T. Gilbert et al. / Biochimie 93 (2011) 2126e2131
Fig. 1. Overview of renal organogenesis in vertebrates. A. Three successive embryonic kidneys appear throughout renal organogenesis. Pronephros and mesonephros are functional kidneys of the larval and adult amphibian, respectively. In mammals, the pronephros is vestigial, the mesonephros is the embryonic form of the kidney and the metanephros will form the definitive kidney. Formation and extension of the nephric duct along the nephrogenic chord dictate the appearance of the successive kidneys. The mesonephric tubules located in a more rostral position are connected to the nephric duct, as opposed to the second set of mesonephric tubules that are in a more caudal position. The ureteric bud outgrowth interacts with the metanephric mesenchyme and initiates metanephros formation, characterized by active UB branching morphogenesis and exponential nephron induction. The mesonephros will then start to degenerate. The vascular pole in each type of kidney is represented by a red dot. B. Whole mount in situ hybridization of SMP-30 in late tadpole stage Xenopus laevis embryo. On this lateral view the expression of SMP-30 is clearly restricted to the pronephros, with a very strong labelling of the pronephric tubules and a faint signal present in the nephric duct. Inset shows the prominent staining in the proximal tubules. C. Whole mount immuno-detection of Calb1 protein in embryonic day 13.0 mouse metanephros. Staining is present in the entire ureteric bud epithelium, from its most distal part to every tip. MM, metanephric mesenchyme; MT, mesonephric tubule; NC, nephrogenic chord; ND, nephric duct; UB, ureteric bud; Bars represent 1 mm and 0.1 mm in B and C, respectively.
duct and the nephrogenic chord continue to extend, the cranial mesonephrons start to degenerate. Then the metanephros or final kidney arises when an outgrowth of the nephric duct named the ureteric bud interacts with the caudal end of the nephrogenic chord. Signals between the epithelial bud and the metanephric mesenchyme lead to an active branching morphogenesis of the former and condensation of the latter around the extremities of the dividing ureteric bud. This condense mesenchyme differentiates into a renal corpuscule, comprising a glomerular and a tubular segment that will differentiate into a nephron that connects to the growing ureteric bud. Several thousands of nephrons will then be generated. The arborisation of the ureteric bud can therefore be viewed as an effective way for multiplying the sites of nephron induction within the metanephrogenic mesenchyme. However, as opposed to the mesonephros, no formation of new nephron can occurred in mammals when nephrogenesis is completed. According to mammalian species, nephron endowment is acquired in
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utero or a few days postnatally, and plasticity of nephron number is the rule in every species [7]. Taking advantages of the experimental accessibility of frog and chick embryos and of genetically modified murine models, it became apparent that the molecular mechanisms involved in development and patterning of the pronephros, mesonephros and metanephros are remarkably conserved within vertebrates. The specification of the pronephric territory is the key event that delineates all successive steps of renal organogenesis. It occurs very early in amphibian, at the end of gastrulation, and the first morphological changes are observed by mid-neurula within the prospective pronephric area in the vicinity of the fifth to sixth somite. In the mouse, at embryonic day 8.5 (E8.5), the pronephros is barely detectable and levels with presumptive somites 5e8. Similar inductive events, signalling cascades and gene products have been shown to drive pronephric to metanephric differentiation [8,9]. The early expression of several transcription factor families, such as Osr, lhx and Pax, characterizes the pronephros field [10,11]. Delineation of its identity and definition of its size are dependent on the Irx family of homeogenes [12] while expression of the transcriptional repressor Tbx2 has just been proposed to control the boundary of the pronephric territory [13]. Specification of the nephric lineage is then dependent upon Pax genes [14]. The formation of the nephric duct primordium that extends caudally is the critical event for the formation of both meso- and meta-nephros. If little is known on the molecular strengths and signals that contribute to the elongation of the nephric duct, the specification of the intermediate mesenchyme towards a mesonephric or metanephric phenotype is largely dependent upon its antero-posterior patterning by Hox11 genes. As shown by Mugford and colleagues, the homeogene Hoxd11 activates the Six2 transcription factor that is required for the acquisition and maintenance of metanephric progenitors [15]. In conjunction with Eya genes family, the gene network Pax/Six/Eya specifies the metanephric lineage. For a more detailed update on early renal cell fate determination, the reader can refer to [16]. 2. Calcium signalling is present throughout kidney development Calcium (Ca2þ) is an intracellular messenger involved in a variety of signalling processes, from signal transduction to transcription, from cell division to apoptosis, from differentiation to oncogenesis. The wealth of events in normal function and disease controlled by calcium is overwhelming [17]. Recent studies based upon Ca2þ imaging in various animal species have demonstrated that Ca2þ signals are associated with many of the sequential steps and processes that are common to animal development. During early vertebrate development, Ca2þ pulses, waves and gradients have been recorded. It is now acknowledged that they are involved in coordination of cell movements, axis specification and the development of the nervous system, heart and muscle (for review see [18,19]). Regarding kidney development, it must be acknowledged that calcium signalling has been largely ignored although specific labelling of embryonic kidneys by calcium-binding proteins was one of the most commonly used methods to assess pronephros and metanephros development (Fig. 1). In frog larvae, the senescence marker protein-30 (SMP-30), also named regucalcin, is a highly conserved Ca2þ binding protein and is selectively expressed in pronephric tubules [20]. It labels strongly the proximal tubules and to a lesser extent the intermediate segment (Fig. 1B). Its expression in cortical collecting duct of E15 mouse kidney has also been reported from microarray expression profiles [21]. In murine development, renal expression of calbindin-D28k (calb1) is a standard marker for ureteric bud and embryonic collecting duct (Fig. 1C). Calb1 expression starts in cells of the
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mesonephric duct at E11 in the mouse and E13 in the rabbit, and is then observed in the metanephric duct [22,23]. High levels of Calb1 were also found in the developing chick kidney, in mesonephric distal and connecting tubules, and subsequently in the Wolffian duct [24]. Data highly suggest that the expression of Calb1 overlaps with the formation of the mesonephros, i.e. when the nephric duct induces among nephrogenic cells a mesenchyme to epithelium transition. To this respect, the appearance of Calb1 expression at the most posterior end of the connecting tubule in the pronephros is revealing [3]. And it is noteworthy that the high expression of Calb1 at site of nephron formation stops upon cessation of nephrogenesis to become restricted to the distal tubule [25]. Beside these two well characterized renal markers, two additional calbindins are expressed in the developing kidneys (Table 1). Calretinin or calb2 is expressed in mesonephric tubules [24] and calbindin-D9k also called calb3 is expressed later in the metanephric kidney in convoluted distal tubules [15,22]. Calbindin 1 and 2 belong to a subset of cytosolic proteins of the EF-hand family and both display the typical helix-Ca2þ binding loop-helix structure. Calb3 on the other hand is a member of the large S100 family. All three calbindins are considered as true Ca2þ buffers as well as the first isolated Ca2þ binding protein of the EF-hand family, parvalbumin [26]. This latter has barely been studied during kidney development. One report mentions its expression within collecting duct and distal tubules of human embryonic metanephros [27]. None of the transgenic mouse strains with altered calbindin(s) or parvalbumin expression display a distinguishable renal phenotype, likely due to compensatory molecular regulation of Ca2þ homeostasis. However, the use of parvalbumin as a strong diagnostic marker for renal neoplasms, specifically chromophobe renal cell carcinoma, is suggestive of an altered calcium signalling in those collecting duct-derived tumours that show no expression of calb1 and 2 [27]. The role of parvalbumin during early kidney development cannot be fully excluded since abundant parvalbuminimmunoreactive materials in proximal tubules along the frog kidney have been reported [28]. Most of the Ca2þ binding proteins are rather classified as Ca2þ sensors. The prototypical example calmodulin does not exhibit specific expression domains throughout renal organogenesis, consistent with its role as a ubiquitous Ca2þ sensor. Calreticulin or calregulin, is another good example of an expression very early during kidney organogenesis as reported in fish pronephros [29]. Upon conversion of the metanephric mesenchyme into nephron,
calretinin expression is significantly enhanced in newly formed epithelial structures [30]. As reported in Table 1, additional S100 and proteins containing EF-hand Ca2þ binding domain (S100A5, S100B, Efcab1 and Gca) are expressed in the developing murine nephric duct at E10.5 and in the ureteric bud and derivatives [21]. Among these proteins, S100B can interact with the tumour suppressor p53 to regulate its tetramerization and transcriptional activity in a Ca2þ dependent manner [31,32]. Since p53 is a known regulator of metanephric development [33] one may propose that Ca2þ-bound S100B contributes to metanephros formation. Among the annexin family that are Ca2þ dependent phospholipid binding proteins, the annexin IV turned out to play an important role in pronephros morphogenesis [34]. Absence of annexin IV at the luminal pronephric tubule surface lead to enlarged pronephric tubule, indicating that annexin IV is involved in regulation of passive membrane permeability to water and protons, as suggested in vitro [35]. Another member of the annexin family, annexin 11 (anxa11), is selectively present in the ureteric bud and collecting duct within E15.5 mouse kidney. This restricted expression profile brings a supplementary clue for the likely participation of anxa11 to Ca2þ homeostasis via membrane traffic and/or regulation of ion channels activities events in the developing metanephros [36]. 2.1. Calcium, a necessary signal for renal progenitors In Xenopus embryo, the presumptive pronephros territory at early tailbud stage can be specifically labelled by NDRG1, a member of the N-myc downstream-regulated gene family. The depletion of xNDRG1 causes failure of pronephros development [37]. One of the signals that modulate NDRG1 expression is an intracellular rise in Ca2þ [38]. This prompts us to study the intracellular Ca2þ dynamics in Xenopus embryos and analyze their effects on pronephros formation. Using the bioluminescent Ca2þ sensitive photoprotein aequorin combined with photon imaging microscope, our group has recently demonstrated that Ca2þ is a necessary signal to trigger pronephric tubule differentiation [39]. First we showed that in intact embryo, Ca2þ transients peak shortly after completion of gastrulation and gradually decrease. Several successive waves of Ca2þ are observed in the pronephric territory at each steps of pronephros formation, from gastrula to early tailbud stage, when the pronephros anlage emerges from the intermediate mesoderm. Second, by injecting an inactive caged Ca2þ chelator diazo-2 in the lateral marginal zone of 4-cell stage embryo with EGFP mRNA as
Table 1 Expression of Ca2þ buffers and Ca2þ sensors during renal organogenesis. Common names
Gene symbol
Pronephrosa
Mesonephrosa
Metanephrosa
References
Regucalcin, SMP-30 Calbindin-D28k Calretinin Calbindin-D9k, Calb3, S100g Parvalbumin
Rgn Calb1 Calb2/CR Calb3/S100g Pvalb
PT (Xl) CT (Oc) nd nd PT (Xl)
nd MT, ND (Gg, Oc) MT, CT (Gg) nd nd
cCD, UT UB, CD, DT PT (Gg) DT CD, DT (Hs)
[20,21] [22e24] [24] [15,22] [27,28]
Calreticulin, calregulin S100 Ca2þ binding protein A5 S100 Ca2þ binding protein B EF-hand Ca2þ binding domain 1 Grancalcin Annexin A4 Annexin A11 Calcineurin A
Calr S100a5 S100b Efcab1 Gca Anxa4 Anxa11 Ppp3ca
þþ (Om) nd nd nd nd PT nd nd
nd nd nd ND E10.5 nd nd nd nd
RC, PT, DT (Rn) mCD UB E10.5 UB E10.5 UT, cCD, RI nd UB, cCD, mCD CM, RI
[29,30] [21] [21] [21] [21] [34] [21] [21,52]
cCD, cortical collecting duct; CD, collecting duct; CT, connecting tubule; mCD, medullary collecting tubule; CM, cap mesenchyme; DT, distal tubule; PT, proximal tubule; MT, mesonephric tubule; ND, nephric duct; RC, renal corpuscule; RI, renal interstitium; UB, ureteric bud; UT, ureteric tip. þþ: highly expressed. nd: not documented. Gg, Gallus gallus; Hs, Homo sapiens; Oc, Oryctogalus cuniculus; Om, Oncorhynchus mykiss; Rn, Rattus norvegicus; Xl, Xenopus laevis. a Data are limited to E15.5 murine metanephros unless other specification.
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tracer, we demonstrated that uncaging diazo-2 in the pronephric domain, prior to the first sign of pronephric differentiation produced embryos with a shortened and widened pronephric tubule. An increase in intracellular calcium is therefore required to allow optimal tubule differentiation in the amphibian kidney. The question then arises if a similar evolutionary conserved mechanism occurs in the metanephros of higher vertebrates. N-myc is highly expressed in the induced metanephric mesenchyme, and is a feature of early differentiation since its expression decreases dramatically during differentiation [40]. N-myc is an important regulator of rapid cell proliferation in the cap mesenchyme. Reduction in N-myc protein levels lead to renal hypoplasia secondary to a decrease in cell proliferation [41] whereas enhanced expression was commonly observed in nephroblastoma or Wilms’ tumours [42]. Very few publications are available on NDRG family members in metanephros development. In situ hybridisation data from the GUDMAP renal expression database show that Ndrg1 is expressed in the metanephric mesenchyme and early tubule when Ndrg2 is restricted to the cap mesenchyme [21]. In clear cell renal cell carcinoma NDRG2 expression is significantly lower than in normal renal tissues, consistent with its proposed role of a tumour suppressor [43]. It is therefore tempting to propose that N-myc downstream-regulated gene expression in embryonic mouse kidney may occur in conjunction with an intracellular rise of Ca2þ in vivo. To this regard, the recent recording of repetitive calcium waves in metanephric blastema cells of explanted embryonic rat kidney [44] provides a significant breakthrough towards a more consensual requirement of Ca2þ for kidney development, from amphibian to mammalian kidney. This current proposal is even reinforced by the report of cultured human foetal kidney epithelial progenitor cells that maintain a mesenchymal phenotype under low calcium-containing medium [45]. The increase of intracellular calcium in the pool of nephron progenitors following induction brings us to the next question: what are the targets of this signal?
(CnABP), expressed in mesenchymal progenitor cells at the onset of metanephric kidney development was shown to be overexpressed in Wilms’ tumours [53]. The interaction between CnABP and calcineurin A leads to an inhibition of the phosphatase activity and defective NFAT-mediated signalling. During embryonic kidney development, the canonical Wnt/ b-catenin signalling is the major pathway regulating the early step of nephron induction i.e. formation of mesenchymal aggregates [54]. However, the failure to fully rescue the tubulogenesis defects observed in Wnt4 and Wnt9b null mice following overexpression of b-catenin [54] suggests that activation of canonical Wnt signalling can inhibit non-canonical Wnt responses [55]. The current idea is that tubulogenesis per se requires an attenuation of b-catenin signalling [56], consistent with the reduced pronephric tubulogenesis observed upon excess of b-catenin [57]. Among the non-canonical Wnt signalling pathways, the calcineurin/NFAT pathway turned out to be crucial for nephrogenesis with NFATc proteins transducing the Ca2þ signals to the nucleus. The experimental proofs and molecular characterization of calcium-mediated nephrogenesis were brought earlier this year by the groups of A. Perantoni and of P. Hohenstein. The first demonstrated that tubulogenesis in metanephric mesenchyme occurs by a non-canonical Wnt/calcium-dependent mechanism [58]. Wnt4-treated primary metanephric mesenchymal cells exhibited a significant Ca2þ influx leading to tubule formation that was blocked in presence of Ca2þ chelator. The second found that calcium/NFAT pathway functions downstream of Wnt4 in nephrogenesis [59]. Among the NFAT genes, Nfatc3 and Nfatc4 were abundantly expressed in the metanephric mesenchyme. Altogether, these data demonstrated that Ca2þ influx and NFAT signalling not only promote nephrogenesis but that they are also required for complete mesenchymal to epithelial transition during nephron formation.
2.2. Calcineurin/NFAT signalling controls nephron formation
One last example of the involvement of calcium signalling during kidney development is illustrated by the link between calcium-dependent signals and polycystins. Polycystin-1 (PC-1) and -2 (PC-2) are the products of the genes PKD1 and PKD2 that are mutated in many cases of autosomal dominant polycystic kidney disease (ADPKD), characterized by the progressive development of fluid-filled cysts from the tubules and collecting ducts of injured kidneys [60]. PC-1 is a highly glycosylated trans-membrane protein expressed in developing tubular epithelia and distal branches of the ureteric bud [61]. PC-2 is detected earlier, in the mesonephros, before being highly expressed in the ureteric bud and metanephric mesenchyme of the developing human metanephros [62]. Then PC-2 expression became prominent in maturing proximal and distal tubules [63]. Both proteins belong to the transient receptor potential (TRP) superfamily, and are also named TRPP1 and 2. TRPs are cation channels involved in many physiological processes along the nephron (for review see [64,65]). In fact, TRPP1 is not a true cation permeable channel and displays very limited sequence similarity with TRPs. Its classification within the TRPP subfamily is based upon the presence of six membrane-spanning regions at the C-terminus that resemble the PC-2 structure. PC-1 and PC-2 require intact carboxyl termini and the coiled-coil domain to interact with each other. Nevertheless, both polycystins are essential for the establishment and maintenance of epithelial tubular structures in the kidney [66]. Co-assembly of these two polycystin proteins produces new calcium-permeable non selective cation currents, and this channel activity is lost in ADPKD [67]. The PC-1/PC-2 complex localized to the primary cilia functions as a mechanosensitive receptor allowing Ca2þ entry into the cell [68]. In this complex, PC-1 is currently viewed as a polymodal receptor that
Clues about the unsuspected role of calcium-mediated mechanisms in metanephric nephron formation came first from studies investigating the potential toxicity of cyclosporin A (CsA) during kidney development. CsA is a potent immuno-suppressive drug that interacts with calcineurin, a protein phosphatase that is activated upon calcium/calmodulin binding. This interaction prevents the dephosphorylation of cytosolic NFAT (Nuclear Factor of Activated T cells) and its nuclear translocation, leading to transcriptional modifications of genes expressions (for review see [46]). The original observation of a link between calcium and nephrogenesis was made on rat metanephros organ culture. We showed that the presence of the calcineurin inhibitor CsA in the culture medium was deleterious to in vitro nephron induction in a dose-dependent manner [47]. Because an unaltered branching pattern of the ureteric bud was observed, the nephron deficit was likely to result from an impaired capacity of the mesenchyme to convert into epithelium [48]. These data were validated in vivo in a rabbit model of in utero exposure to CsA. Upon CsA administration simultaneous to the onset of renal organogenesis, a permanent nephron deficit was obtained in every pup [49]. Long term follow-up indicated a progressive chronic renal insufficiency in adulthood and systemic hypertension [50]. Additional calcineurin inhibitors have been shown to affect the development of pronephric tubules in Xenopus [51]. Therefore it became apparent that calcineurin-dependent pathway was involved in the developing kidney. This was confirmed in knockout mice for calcineurin A that display an absence of proliferation and a defective maturation of the nephrogenic zone [52]. More recently, a calcineurin A-binding protein
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controls the channel activity of PC-2 [69]. Other cellular locations have been reported for each polycystin, notably the basolateral plasma membrane for PC-1 and the endoplasmic reticulum for PC-2. This indicates that cilia-mediated mechanosensory stimuli are not the only mechanism implicating polycystin, but few investigations have addressed this issue. Additional Ca2þ channel proteins can also associate with PC-2, namely TRPC1 and TRPV4, to form polymodal sensory channel or hetero-complexes [70,71]. The strong expression pattern of TRPC1 in the embryonic proximal tubules and the restricted expression of TRPV4 to the ureteric bud tip epithelium suggest that a similar association with PC-2 may occur during kidney development [21]. One of the triggering events in regulating cellular Ca2þ homeostasis via intracellular Ca2þ pools seems to be the direct interaction of PC-2 with the type I inositol 1,4,5-triphosphate receptor [72]. Polycystin-2 downstream signalling pathway involves activation of intracellular Ca2þ release channels, especially the ryanodine receptor [73]. Attention has been focused on calcium in ADPKD because it is the most proximate signal to the PC-1/PC-2 complex. However, the role of Ca2þ signalling in the molecular mechanisms of cystogenesis in PKD is far from being understood. The ability of PC-1, independently of PC-2, to activate the calcineurin/NFAT signalling pathway via activation of the phospholipase C [74], further indicates that defects in Ca2þ transients leading to abnormal kidney development and cyst formation may occur via multiple signalling cascades. 3. Conclusions Increasing lines of evidence have highlighted calcium as a necessary signal for conversion of the pronephric and metanephric mesenchyme into a functional nephron epithelium. The triggering of the initial renal territory depends on calcium transients and the requirement upon calcium for mesenchyme to epithelium transition is now clearly demonstrated. Throughout renal organogenesis intracellular Ca2þ must therefore be tightly regulated. The presence of SMP-30 and Calbindin-D28k involved mostly in the efflux of Ca2þ across the plasma membrane confirms the need for a balanced calcium environment. Future research directions will be aimed at identifying members of the calcium homeostasome that participate in kidney development, and at determining the precise downstream targets of calcium-dependent signalling. New crosstalks between calcium and other signalling pathways will certainly be unveiled. References [1] L. Saxén, Organogenesis of the Kidney, vol. 19, Cambridge University Press, Cambridge, 1987. [2] P.D. Vize, E.A. Jones, R. Pfister, Development of the Xenopus pronephric system, Dev. Biol. 171 (1995) 531e540. [3] D. Raciti, L. Reggiani, L. Geffers, Q. Jiang, F. Bacchion, A.E. Subrizi, D. Clements, C. Tindal, D.R. Davidson, B. Kaissling, A.W. Brändli, Organization of the pronephric kidney revealed by large-scale gene expression mapping, Genome Biol. 9 (2008) R84. [4] N. Watanabe, M. Kato, N. Suzuki, C. Inoue, S. Fedorova, H. Hashimoto, S. Maruyama, S. Matsuo, Y. Wakamatsu, Kidney regeneration through nephron neogenesis in medaka, Dev. Growth Differ. 51 (2009) 135e143. [5] W. Zhou, R.C. Boucher, F. Bollig, C. Englert, F. Hildebrandt, Characterization of mesonephric development and regeneration using transgenic zebrafish, Am. J. Physiol. Renal Physiol. 299 (2010) F1040eF1047. [6] K. Sainio, P. Hellstedt, J.A. Kreidberg, L. Saxén, H. Sariola, Differential regulation of two sets of mesonephric tubules by WT-1, Development 124 (1997) 1293e1299. [7] C. Merlet-Benichou, T. Gilbert, J. Vilar, E. Moreau, N. Freund, M. LelievrePegorier, Nephron number: variability is the rule e causes and consequences, Lab. Invest. 79 (1999) 515e527. [8] A.W. Brändli, Towards a molecular anatomy of the Xenopus pronephric kidney, Int. J. Dev. Biol. 43 (1999) 381e395. [9] G.R. Dressler, The cellular basis of kidney development, Annu. Rev. Cell Dev. Biol. 22 (2006) 509e529.
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