Hepatocyte growth factor in renal failure: Promise and reality

Kidney International, Vol. 57 (2000), pp. 1426–1436

PERSPECTIVES IN BASIC SCIENCE

Hepatocyte growth factor in renal failure: Promise and reality GUSTAVO A. VARGAS, ANDREAS HOEFLICH, and PETER M. JEHLE Department of Internal Medicine II, Division of Nephrology, University of Ulm, Ulm, and Institute of Molecular Animal Breeding, Gene Center, Munich, Germany

Hepatocyte growth factor in renal failure: Promise and reality. Can science discover some secrets of Greek mythology? In the case of Prometheus, we can now suppose that his amazing hepatic regeneration was caused by a peptide growth factor called hepatocyte growth factor (HGF). Increasing evidence indicates that HGF acts as a multifunctional cytokine on different cell types. This review addresses the molecular mechanisms that are responsible for the pleiotropic effects of HGF. HGF binds with high affinity to its specific tyrosine kinase receptor c-met, thereby stimulating not only cell proliferation and differentiation, but also cell migration and tumorigenesis. The three fundamental principles of medicine—prevention, diagnosis, and therapy—may be benefited by the rational use of HGF. In renal tubular cells, HGF induces mitogenic and morphogenetic responses. In animal models of toxic or ischemic acute renal failure, HGF acts in a renotropic and nephroprotective manner. HGF expression is rapidly up-regulated in the remnant kidney of nephrectomized rats, inducing compensatory growth. In a mouse model of chronic renal disease, HGF inhibits the progression of tubulointerstitial fibrosis and kidney dysfunction. Increased HGF mRNA transcripts were detected in mesenchymal and tubular epithelial cells of rejecting kidney. In transplanted patients, elevated HGF levels may indicate renal rejection. When HGF is considered as a therapeutic agent in human medicine, for example, to stimulate kidney regeneration after acute injury, strategies need to be developed to stimulate cell regeneration and differentiation without an induction of tumorigenesis.

Growth factors are involved in multiple responses such as cell proliferation, differentiation, and motility mediating their effects via receptor tyrosine kinases [1, 2]. The type of response triggered depends on receptors and ligands that are differentially expressed by various cell types. This review focuses on the structure, function, and

Key words: growth factors, HGF, cell proliferation, tumorigenesis, nephroprotection, renotropic growth factor. Received for publication June 29, 1999 and in revised form October 18, 1999 Accepted for publication November 2, 1999

 2000 by the International Society of Nephrology

possible therapeutic applications of hepatocyte growth factor (HGF) and its receptor, c-met [3–5]. HEPATOCYTE GROWTH FACTOR/SCATTER FACTOR STRUCTURE AND SYNTHESIS The biological features of HGF are summarized in Table 1. Previous studies described several mitogenic and motogenic polypeptides that were identified later as HGF [6–9]. Independently, the existence of a polypeptide secreted by embryonic fibroblasts was reported that promotes the scattering of Madin-Darby canine kidney (MDCK) and other epithelial cells by paracrine mechanisms [10–12]. This polypeptide was named scatter factor (SF) [13] and was later on identified as HGF [14–18]. Simultaneously, fibroblast tumor cytotoxic factor (F-TCF) [19] and the broad spectrum mitogen produced by lung fibroblasts [20] were also found to be identical to HGF. The human HGF gene is localized on chromosome bands 7q11.2-21 [14]. The HGF gene promoter contains positive and negative regulatory elements and is highly conserved among human and rodent species [21]. Native HGF is secreted as an inactive precursor (pro-HGF), which is converted to the active form after extracellular proteolysis by several activators [22–25] and in response to tissue injury [26]. HGF activation could be inhibited by a specific serine protease inhibitor [27]. It has been suggested that HGF, macrophage stimulating protein (MSP; a growth factor with biological effects similar to HGF), apolipoprotein-a, and plasminogen have evolved from a common ancestral gene [28, 29]. Two truncated variants of HGF containing the N-terminal region and the first (HGF/NK1) or the first and the second (HGF/NK2) kringle domains are generated by alternative splicing. NK2 behaves as an HGF antagonist [30]. NK1 is derived from a 2.2 kb transcript [4] and is able to exhibit agonistic and antagonistic actions [30–33]. In hepatocytes, NK1 acts primarily as an HGF antagonist [34] but elicits an agonistic response in the presence of heparin [35]. NK1 transgenic mice reveal the typical phenotype of HGF transgenic mice, underscoring its agonistic action in vivo [36]. A shorter synthetic HGF variant, HGF/NK4, can act as an antagonist [37].

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Vargas et al: HGF in renal failure Table 1. Synopsis on biologic features of hepatocyte growth factor (HGF) Synonymous polypeptides • fibroblast tumor cytotoxic factor (F-TCF) • hepatocyte growth factor (HGF) • hepatopoietin A • hepatotropin • scatter factor (SF) Related polypeptides • apolipoprotein (a) • blood coagulation factor XIIa • macrophage-stimulating protein (MSP) • plasminogen Biologic effects • mitogen • morphogen • motogen • inductor of tubulogenesis • promotor of invasiveness HGF gene localization • human chromosome 7, bands 7q11.2-q21 Polypeptide characteristics • monomeric inactive precursor (pro-HGF) • heterodimeric form (␣/␤-chain) after proteolytic cleavage (728 aa) • various isoforms (truncation, alternative splicing) • four kringle domains • one inactive serine protease domain • four potential glycosylation sites • heparin and glycosaminoglycans binding sites HGF expression • during organ development (e.g., kidney, liver, trophoblast) • in adult life in tissue of mesodermal origin (e.g., fibroblasts, blood mononuclear cells, platelets)

HEPATOCYTE GROWTH FACTOR RECEPTOR BINDING AND SIGNALING The HGF receptor is the product of the c-met protooncogene [38]. A synopsis on the biological features of c-met is given in Table 2. The c-met product is a tyrosine kinase receptor [39–43] with two disulfide-linked subunits and a single noninterrupted kinase domain sharing homology with the src family of tyrosine kinases (Fig. 1). The c-met tyrosine protein kinase oncogene family is related to cell invasiveness and comprises v-ros, the insulin-like growth factor (IGF)-I receptor, the 220 kD SEX protein, Ron (MSP receptor), and Sea (sarcoma, erythroblastosis, and anemia; unknown ligand) [44–49]. Ron and Sea can induce the same biological effects as c-met [47]. After HGF binding and subsequent ligand-induced receptor dimerization, c-met is activated by autophosphorylation (Fig. 1A) [16, 39, 41, 43, 50–52]. The principal site for autophosphorylation is located in the kinase domain at Tyr 1235, which together with Tyr 1230 and Tyr 1234, comprises a common “three tyrosine” motif that is conserved in the insulin and platelet-derived growth factor (PDGF) receptor tyrosine kinases [53]. The phosphorylation of Ser 985 [54] and a protein phosphatase [55] can negatively modulate c-met kinase activity. Experiments with receptor chimeras showed that c-met is the first downstream effector in the HGF signaling cascade [56].

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Table 2. Synopsis on biologic features of c-met Polypeptide features of c-met • product of the c-met proto-oncogene • synonymous polypeptides not known • 190 kD precursor • N-glycosylated mature protein • two disulfide-linked subunits ␣-chain, 50 kD, extracellular location ␤-chain, 145 kD, extracellular, transmembrane and intracellular two major isoforms differing by a 47-aa segment in the juxtamembrane domain single noninterrupted tyrosine kinase domain in the ␤-chain Related polypeptides • Ron tyrosine kinase receptor (ligand MSP) • Sea tyrosine kinase receptor c-met gene localization • human chromosome 7, bands 7q21-q23 Biologic function • receptor unique for HGF c-met expression • almost all epithelia (e.g., kidney, liver, stomach, small intestine, brain, breast) • endothelial cells • increased expression in several carcinoma

A specific Tyr at position 1356 in the C-terminal tail is needed for cell motility and morphogenesis [57]. Heparin or similar extracellular matrix compounds can modulate HGF binding and action [58, 59]. Heparin-like molecules can stabilize HGF oligomers and enhance the mitogenic potency, probably by facilitating c-met receptor dimerization and activation [60], whereas heparan sulfate proteoglycans act as negative modulators [61]. EXPRESSION OF HEPATOCYTE GROWTH FACTOR AND c-met AND BIOLOGICAL EFFECTS Hepatocyte growth factor is expressed in tissues of mesodermal origin [62], whereas c-met is expressed in epithelia, including liver and kidney [63], and in several human carcinomas [64]. Steroid hormones, cytokines [tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1, IL-6], and basic fibroblast growth factor (bFGF) regulate HGF and c-met expression [5, 65, 66]. According to the findings in double transgenic HGF/transforming growth factor (TGF)-␣ mice, HGF produces a partially inhibitory effect on hepatocellular carcinogenesis induced by TGF-␣ [67]. Furthermore, HGF can reverse the arrest on cell growth induced by TGF-␤ [68], whereas TGF-␤ was shown to enhance the motogenic effects of epidermal growth factor (EGF) but not HGF [69]. EGF can negatively modulate HGF-induced cell migration [70]. In contrast, the HGF-induced increase in DNA synthesis in hepatocytes of HGF-transgenic mice is intensified by EGF or insulin, and the growth inhibitory effects of TGF-␤ are depressed [71]. Besides its renotropic action (vide infra), HGF exerts pleiotropic biological effects on different cell types. At

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Vargas et al: HGF in renal failure Table 3. Role of HGF/c-met in kidney Organogenesis • HGF or c-met knockout mice die in utero before any kidney abnormality appears In vitro effects • increase of DNA synthesis in kidney epithelial cells • scattering • invasiveness in collagen cells In vivo effects • promotes the recovery of renal function after ischemia unilateral nephrectomy chemical-induced renal damage In human kidney disease • mutations in c-met are associated with hereditary papillary renal carcinoma • c-met is increased in most of the renal carcinomas • possible link between HGF overexpression and renal cysts • possible association between c-met up-regulation and diabetic renal hypertrophy

least some of the biological effects of HGF are due to inhibition of apoptosis [72, 73]. HGF is a potent mitogen for hepatocytes and is crucial for liver development [74– 76]. Transgenic mice expressing HGF under the control of the albumin promoter performed liver regeneration two times faster than normal mice [77], whereas tumors of diverse origin were found in HGF transgenic mice under the control of the metallothionein promoter [78]. On the other hand, in c-myc/HGF double transgenic mice, hepatic tumorigenesis induced by c-myc is prevented by HGF [79]. HGF-expressing fibroblasts prevent the onset of acute liver damage induced by CCl4 or bacterial lipopolysaccharide when transplanted into the spleen of rats [80]. Elevated HGF levels have been reported after partial liver resection, acute or chronic hepatitis, and fulminant liver failure [81, 82]. In acute hepatitis, serum HGF levels are approximately twofold higher compared with controls [83].

Fig. 1. Molecular structure of the hepatocyte growth factor (HGF) receptor c-met (A) and signal transduction (B). (A) The c-met product (left) is a tyrosine kinase receptor of 190 kD with two disulfide-linked subunits, a 50 kD extracellular ␣-chain (␣) and a 145 kD ␤-chain (␤). HGF binding induces receptor dimerization (middle) and autophosphorylation (right). (B) After autoposphorylation in the kinase domain of cmet (Tyr1234, Tyr1235; indicated as Y in the white box), a downstream located multifunctional docking site (Tyr1349, Tyr1356) in the C-terminal domain mediates the signal to multiple transducers, including PI3 kinase, the Grb2/Sos/Ras complex, the IRS-like multiadaptor protein Gab-1, phospholipase-␥, and probably Src. The pleiotropic effects of HGF are mediated via different signaling pathways, which may differ in various cell types.

HEPATOCYTE GROWTH FACTOR, c-met, AND THE KIDNEY The role of HGF and c-met in the kidney is summarized in Table 3. During perinatal kidney development in rats, diverse receptor tyrosine kinases and growth factors are expressed or activated including c-met and HGF [84]. In mouse metanephros at embryonic day 11, HGF is expressed primarily in the mesenchyme, whereas c-met is found also in the ureteric bud [85]. An important role of HGF during branching morphogenesis of the ureteric bud has been suggested by several cell culture studies [85, 86]. HGF stimulates epithelial differentiation of metanephric mesenchymal cells [87]. The formation of HGF/SF-induced branching tubules in MDCK cells cultured in collagen gels is connected with the induction of membrane type 1 matrix metalloproteinase [88]. At

Vargas et al: HGF in renal failure

Fig. 2. Morphogenic effects of HGF on cultured proximal tubular cells. The differentiated rabbit proximal tubular cell line PT-1 was cultured in Dulbecco’s modified Eagle’s medium (DMEM) as described [94, 95]. Cells were incubated for 48 hours in serum-free medium alone (A; bar ⫽ 10 ␮m) or in the presence of HGF (10⫺9 mol/L; B). HGF induced cell scattering (thin arrows) and tubulogenesis (thick arrows). Reprinted with permission from Jehle et al [94].

the first stages of kidney tubulogenesis, other growth factors may replace the morphogenetic role of HGF. c-met knockout kidney cells form tubules in vitro upon stimulation with TGF-␣ [89]. Another study showed that TGF-␣ and EGF induce tubulogenesis of murine inner medullary collecting duct cells [90]. Coculture experiments revealed that HGF produced by mesangial cells stimulates endothelial cell growth and that this interaction is negatively modulated by TGF-␤ and angiotensin II [73]. These authors suggested that negative regulation of local HGF production by both factors may play an important role in the pathogenesis of renal disease. The morphogenetic and motogenic effects of HGF were first described in the MDCK cell line [91] and were confirmed in a variety of other epithelial cells [92–94]. In differentiated rabbit proximal tubular cells, HGF exhibits potent mitogenic, morphogenetic, motogenic, and epithelial cell-differentiating effects under serum-free conditions [95]. Among its pleiotropic effects, the induction of cell scattering plays a pivotal role (Fig. 2). Scatter-

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ing is based on the ability of HGF to inhibit junctional communications, to enhance proteolysis of connexin 43 [96], and to change the phosphorylation patterns of junctional molecules, thereby increasing their stability [97]. In MDCK cells transformed with SV40 large T antigen, scattering is specifically triggered via inactivation of retinoblastoma protein inducing an HGF autocrine loop [98]. In renal epithelial cells, the ectopic overexpression of HGF is able to up-regulate the level of c-met and to stimulate cell scattering [99]. The pleiotropic effects of HGF are mediated via different signaling pathways, which may show differences in various cell types. In all cases, a multifunctional docking site (Tyr at position 1349 and 1356 in the C-terminal domain) mediates the signal of activated c-met receptors to multiple transducers (Fig. 1B), including PI3 kinase, the Grb2/Sos/Ras complex, the insulin receptor substrate (IRS)-like multiadaptor protein Gab-1, and probably Src [100–102]. It is important to note that c-met–mediated biological effects can be dissected on the basis of different signaling requirements [100]. In MDCK cells, HGFinduced cell scattering is dependent on the Ras–mitogenactivated protein kinase (MAPK) signaling pathway [103]. In rabbit proximal renal tubular cells, we demonstrated that the growth-promoting effects of HGF involve the activation of Src, whereas the HGF-induced tubulogenic differentiation (for example, formation of long microvilli at the apical cell membrane) was not influenced by src-interfering tyrosine kinase inhibitors [95]. Invasive cell growth upon stimulation of c-met requires the concomitant activation of Ras and PI-3 kinase [49] or Src and PI3 kinase [104]. Scattering needs PI3kinase activation [105–107] and in some cell types also requires an additional effector [108]. Morphological changes induced by HGF in MDCK cells are related to modifications in cell polarity with alteration of synthesis rate and interaction between ␤-catenin and E-cadherin [109]. The cell spreading response in this model is dependent on the activation of the small guanine 5⬘-triphosphate (GTP)-binding proteins Ras and Rac. PI3 kinase is also involved in mediating the effects of HGF on tubulogenesis [110]. In MDCK cells, HGF-induced tubulogenesis and branching are enhanced by several components of the cell matrix, such as laminin, fibronectin, and entactin, but are inhibited by type IV collagen, heparan sulfate proteoglycan, vitronectin, and TGF-␤ [111]. In these cells, the branching development is regulated by phosphorylation processes mediated by protein kinase A (PKA), protein kinase C (PKC), and Ca2⫹/calmodulindependent kinases [111]. Another protein involved in the scattering and tubulogenesis mediated by HGF in kidney cells is the membrane-cytoskeleton linker ezrin, which is phosphorylated by c-met [112]. Downstream of Grb2 [106], the tubulogenic HGF response is dependent on the STAT pathway [113].

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Fig. 3. Stimulation of c-met gene expression by cytokines and growth factors in cultured renal epithelial cells. Mouse inner medullary collecting duct epithelial cells (mIMCD-3) were incubated for 24 hours in serum-free medium without (control) or with specific cytokines or growth factors at a concentration of 10 ng/mL. The total cellular RNA was isolated and hybridized using rat c-met cDNA as a probe. The same blot was stripped and reprobed with GAPDH to confirm equal loading of the RNA. Similar results were obtained using proximal tubule-derived opossum kidney epithelial cells. Reprinted with permission from Liu et al [116].

Evidence that HGF may represent an important renotropic growth factor came from cell culture studies, animal experiments, and findings in human kidney disease. HGF promotes DNA synthesis of several renal cell types, including tubular and glomerular epithelial cells [94, 114, 115]. The mitogenic effects of HGF on renal tubular epithelial cells are regulated by cell–cell interactions [114]. DNA synthesis stimulated by HGF was high at a low cell density and was strongly suppressed at a higher one. These results suggest that HGF may act not only as an inductor, but also as a modulator in renal regeneration and compensatory renal growth. In conditions of renal injury mediated by folic acid treatment, HGF up-regulates c-met in a tissue-specific manner, acting primarily at the transcriptional level by stimulating the c-met promoter activity [116]. This study also demonstrated up-regulation of c-met expression in renal epithelial cells in vitro by interleukins, TGF-␤, EGF, insulin-like growth factors (IGFs), and platelet-derived growth factor (PDGF) (Fig. 3). Because tissue regeneration results from the integration of the complex interplay among many different growth factors, c-met seems to be at a convergence point and may play a key role in the processes leading to the completion of the entire regenerative course. In the adult mouse kidney, in situ hybridization experiments localized c-met in proximal and distal tubules [63]. During experimental acute renal failure, elevated HGF mRNA levels were found in kidney and liver, but c-met mRNA was upregulated selectively at the site of greatest tubular injury or hypertrophy [117]. HGF mRNA and peptide levels increases in kidney and spleen in response to unilateral

nephrectomy or partial hepatectomy [118]. An increase of HGF and its mRNA was also detected in rats after unilateral nephrectomy and CCl4 treatment, with concomitant internalization of c-met [119], and a transient increase of HGF precedes the regenerating events in rat kidney after vitamin E depletion combined with glutathione depletion [120]. HGF and HGF mRNA increase in rat kidney after ischemia or HgCl2-induced nephrotoxicity and levels remain augmented during the phase of tubular regeneration [121]. On the other hand, the renal expression of c-met increases in rats after ischemia, unilateral nephrectomy, or folic acid treatment [122]. A link between renal hypertrophy observed in diabetic rats was also proposed in relationship with the elevation of c-met in medullar and cortical tubular epithelium [123]. A spontaneous mouse model of chronic renal disease [immune complex glomerulonephritis (ICGN) strain developing glomerular sclerotic injury, tubular atrophy, and renal dysfunction until 17 weeks of age] was used to investigate whether HGF may inhibit the progression of tubulointerstitial fibrosis [124]. When recombinant HGF was injected into these mice during a four-week period (from weeks 14 through 17 after birth), DNA synthesis of tubular epithelial cells was found to be 4.4-fold higher than in mice without HGF injection, thereby suggesting tubular parenchymal expansion promoted by HGF. Notably, HGF suppressed the expression of TGF-␤ and of PDGF as well as myofibroblast formation in the affected kidney. Consequently, HGF completely inhibited the onset of tubulointerstitial fibrosis and attenuated the progression of glomerulosclerosis, both preventing manifestation of renal dysfunction. From these results, supplement therapy with HGF may be taken into consideration as a novel option for prevention and treatment of chronic renal disease. Increased HGF mRNA transcripts were detected in mesenchymal and tubular epithelial cells of rejecting kidney [125], and elevated serum HGF levels were suggested to indicate renal rejection [126]. Serum HGF levels correlate with serum creatinine in chronic renal failure patients, indicating a response to the organ damage or decreased clearance by the insufficient kidney. In acute renal failure, elevated urine HGF levels are described as consistent with a role for HGF in promoting tubule cell proliferation [127], whereas patients with chronic glomerular or polycystic disease, as well as patients with advanced chronic renal insufficiency and healthy controls, show detectable but low urine HGF levels [127, 128]. Hemodialysis with cellulosic or biocompatible membranes and with or without heparin stimulates the increase of HGF levels in circulation, and serum of dialysis patients induces the HGF production in mononuclear cells and fibroblasts [129]. HGF was also detected in cyst fluids in cases of renal cystic disease, suggesting a possible causal coherence with this pathology [130]. Fur-

Vargas et al: HGF in renal failure

Fig. 4. Endothelin-1 release by cultured proximal tubular (PT-1) cells, coincubated with cyclosporine A and hepatocyte growth factor (HGF, 10⫺8 mol/L) or epidermal growth factor (EGF, 10⫺8 mol/L). Data are means ⫾ SEM, N ⫽ 6. ***P ⬍ 0.001 vs. cyclosporine 50 ␮g/L; ⫹⫹⫹P ⬍ 0.001 vs. cyclosporine 500 ␮g/L. Reprinted with permission from Haug et al [132].

thermore, HGF may be involved in the pathogenesis of inflammatory renal diseases. Rat mesangial cells coexpress HGF and c-met in response to IL-6 stimulation in vitro [131]. In cultured renal proximal tubular cells, we showed that HGF potently inhibits the cyclosporine A- or tacrolimus-induced endothelin-1 release (Fig. 4) [132]. Taken together, the above-mentioned studies indicate that HGF, despite its activity on promoting renal regeneration in acute processes, may also be involved in the development of histologic changes associated with the loss of kidney functionality in chronic diseases. HEPATOCYTE GROWTH FACTOR, c-met, AND TUMOR CELL GROWTH Hepatocyte growth factor and c-met are involved in malignant cell growth. HGF transforms immortalized mouse epithelial cells [133], and several lines of evidence suggest that its scatter ability is critical in tumor progres-

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sion. In hepatic nonparenchymal cell lines, HGF transfection produces a loss of cell contact inhibition and the generation of large, invasive tumors in nude mice [134]. Hepatocyte cell lines expressing HGF display the same characteristics [133]. In fibroblasts, simultaneous expression of HGF and c-met is required for tumorigenesis [135]. Bladder carcinoma cells exhibit a scattered phenotype when transfected with HGF and are more invasive than untransfected cells [136]. In renal carcinogenesis, c-met plays a role as an inductor of invasiveness. In 87% of renal carcinomas and in one renal carcinoma cell line, c-met was detected [137]. In SMTK-R3, another renal carcinoma cell line, HGF stimulates not only cell motility and proliferation, but also the glycolipid sulfotransferases activity, indicating multiple biological effects in renal cell carcinomas [138]. In this context, several reports suggested a relationship between the human hereditary papillary renal carcinoma and mutations in the tyrosine kinase domain of c-met [100]. In contrast, both HGF and c-met mRNA levels are normal in nephroblastomas [139]. Abnormal overexpression of HGF produces mesenchymal and epithelial tumors in mice with c-met activation by an autocrine loop [140]. The role of HGF/c-met in tumor progression may be explained in part by an association of the multifunctional docking site of c-met (Fig. 1B) with the anti-apoptotic protein BAG-1 and other substrates [141, 142]. In oral squamous carcinoma cell lines, HGF acts as a promoter of cell migration and invasion with tyrosine phosphorylation of p125FAK kinase [143]. In contrast to these data, the antiproliferative effects of HGF were described in melanoma, squamous carcinoma, and hepatocellular carcinoma cell (HCC) lines [144]. The introduction of an HGF vector in HCCs inhibits cell growth in vitro and diminishes tumor growth in vivo, but stimulates growth of normal hepatocytes [145]. Growth inhibition and induction of apoptosis by HGF have been shown also in transformed rat liver epithelial cells [146]. DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS OF HGF/c-met IN KIDNEY DISEASES A plethora of clinical applications for treatment with HGF or HGF analogue peptides might be raised in the near future [147]. Clinical indications for HGF treatment were suggested in kidney, liver, and lung regeneration, as well as in the treatment of diabetes mellitus, gastric ulcers, and vascular or neuroneal diseases [147]. A recent report describes the reversion of liver cirrhosis in rats injected with an HGF expression vector [148]. Reports connect the severity of arterial hypertension with significantly increased circulating HGF levels, probably as a consequence of endothelial cell damage [149]. A marked elevation of HGF serum levels could also be found in

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the first stages of myocardial infarction but not in other heart diseases [150]. Thus, HGF may be used as a serum marker to monitor the course of myocardium infarction and hypertension-induced endothelial dysfunction. In diverse neoplastic diseases, HGF and/or c-met were also proposed as novel clinical markers of diagnostic or prognostic value. Probably the most exciting possibilities of the clinical utilization of HGF and/or c-met are related to therapy with two basic variants: HGF or c-met blockade in proliferative diseases or HGF-induced tissue regeneration [147]. Protocols including the preadministration of HGF to prevent nephrotoxic side effects of drugs or to induce restoration of functional integrity in diverse tissues after surgical manipulation may be of clinical relevance. Several experimental models indicate a possible therapeutic application of HGF in kidney diseases. In animal models, HGF is at least as potent as EGF or IGF-1 to recover the renal function after acute injury [121, 151]. The administration of HGF accelerates recovery from acute ischemic renal injury in rats by enhancing regeneration of proximal tubular epithelium [152]. In this study, the beneficial effects of HGF on the clinical outcome are indicated by significantly lower creatinine and blood urea nitrogen levels, enhanced insulin clearances, reduced mortality, and much less injury in kidney histologies. Furthermore, the administration of HGF may even prevent acute renal failure when given in a prophylactic manner [121]. HGF not only activates tubular repair processes but also ameliorates the initial injury (for example, cisplatin toxicity) by protecting renal epithelial cells from undergoing apoptosis [72]. It is important, however, to discuss the renoprotective action of administered HGF on the basis of endogenous HGF expression, which changes in acute renal failure. When this condition was induced in rats by ischemia or by HgCl2 administration, DNA synthesis occurred predominantly in the renal tubular cells located in the outer medulla, with a peak at 48 hours after the treatments [153]. In both renal injuries, mRNA levels and activity of HGF in the kidney increased markedly, reaching a maximum 6 to 12 hours after the treatments. HGF was expressed in renal interstitial cells, presumably endothelial cells and macrophages, but not in tubular epithelial cells. In the folic acid rat model of acute renal failure, an extremely rapid induction of renal HGF was observed beginning one hour after the injection of folic acid, with an approximately 16-fold rise in circulating plasma HGF levels [116]. Hepatocyte growth factor may also be of interest in treatment of chronic renal failure. In cultured proximal tubular cells, we recently showed that HGF is more potent than EGF to counteract the cyclosporine- or tacrolimus-induced stimulation of endothelin-1 synthesis and release (Fig. 4) [132]. In the ICGN mouse strain, a model of chronic renal disease, HGF promotes the DNA syn-

thesis in tubular epithelial cells, attenuates glomerulosclerosis, and inhibits almost totally the development of tubulointerstitial fibrosis [124]. In contrast, transgenic mice expressing HGF under control of the metallothionein promoter develop glomerulosclerosis, tubular hyperplasia, and polycystic kidney disease [154]. The same animals show also a marked incidence of tumors of diverse origin [140], probably because of the systemic overexpression of HGF. In fact, in the less affected metallothionein-HGF mice line, the severity of kidney disease is not correlated to the HGF level in serum, but to the liver weight. These findings were interpreted as a contribution of the liver hypertrophy and the systemic HGF levels to the onset of kidney disease in these animals. Finally, our comprehension of the factors involved in the subtle equilibrium between HGF-induced cell and organ regeneration and tumorigenesis is still incomplete, and several problems have to be solved before considering HGF as a therapeutical agent in human kidney disease. The short half-life and fast clearance of HGF from circulation may be overcome by HGF variants with a longer life in circulation [61]. However, the use of such agents may be limited by enhanced systemic side-effects. A therapeutical challenge for the future could be the design of tissue-specific vectors to express HGF in damaged organs, most importantly in kidney during acute renal failure. This could be an approach to avoid the deleterious consequences of systemic HGF expression [140] and to use the amazing biological potency of this renotropic growth factor. ACKNOWLEDGMENTS This work was supported by the Landesforschungsschwerpunkt Baden-Wu¨rttemberg: Modulation von Wachstumsfaktoren als Therapieprinzip (P.M.J.). We thank PD Dr. Cornelia Haug for providing Figure 4. Reprint requests to PD Dr. Peter M. Jehle, University of Ulm, Internal Medicine II, Division of Nephrology, Robert-Koch-Straße 8, 89081 Ulm, Germany. E-mail: [email protected]

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