Acute and chronic effects of growth hormone on renal regulation of electrolyte and water homeostasis

Growth Hormone & IGF Research 17 (2007) 353–368 www.elsevier.com/locate/ghir

Review

Acute and chronic effects of growth hormone on renal regulation of electrolyte and water homeostasis Henrik Dimke a

a,*

, Allan Flyvbjerg b, Sebastian Frische

c

Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University, Geert Grooteplein Zuid 30, Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands b Medical Department M (Diabetes and Endocrinology) and Medical Research Laboratories, Clinical Institute, Aarhus University Hospital, Aarhus, Denmark c The Water and Salt Research Centre, Institute of Anatomy, University of Aarhus, Aarhus, Denmark Received 14 February 2007; revised 29 March 2007; accepted 6 April 2007 Available online 7 June 2007

Abstract For decades, growth hormone (GH) has been known to influence electrolyte and water handling in humans and animals. However, the molecular mechanisms underlying the GH-induced anti-natriuretic and anti-diuretic effects have remained elusive. This review will examine the existing literature on renal electrolyte and water handling following acute and chronic GH-exposure. Renal responses to GH differ in acute and chronic models. Acute application of GH results in a reduced urinary electrolyte and water excretion, whereas the chronic effects of GH are more diverse, as this state likely represents a complex mixture of primary and secondary actions of GH as well as compensatory mechanisms. During chronic GH-exposure an initial sodium retaining state often occurs, followed by a normalization of the urinary sodium excretion, although extracellular volume expansion still persists. We recently described a possible mechanism by which GH acutely increases renal electrolyte and water reabsorption, by modulation of the kidney specific Na+, K+, 2Cl co-transporter (NKCC2). The primary aim of this review is to investigate how GH-induced regulation of NKCC2 may be involved in the complex renal changes previously described during acute and chronic GH. We propose, that the GH-induced increase in NKCC2 activity may explain the initial water and sodium retention seen in a number of studies. Moreover, renal changes seen during prolonged GH-exposure may now be seen on the background of the acute stimulation of NKCC2. Additionally, GH also promotes renal acidification, thus influencing renal acid/base handling. The GH-induced renal acidification is partly compatible with changes in NKCC2 activity. Finally, we review the available data on changes in hormonal systems affecting tubular transport during acute and chronic GH-exposure.  2007 Elsevier Ltd. All rights reserved. Keywords: Growth hormone; IGF-I; NKCC2; Sodium; Thick ascending limb; AQP2

1. Introduction Disturbance of the circadian growth hormone (GH)secretion occurs in several disease states. GH is secreted in a pulsatile pattern throughout the day, but in acromegaly there is an increase in the amplitude and frequency of the pulsatile GH-secretion [1]. GH induces *

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strong anti-natriuretic and anti-diuretic effects [2–5], which likely contributes to a larger than normal extracellular volume (ECV) in acromegalic patients [6]. Similarly, patients suffering from GH deficiency (GHD) have a decreased ECV [7], which can be restored by GH-replacement [8]. In addition, acromegalics often present with symptoms related to a dysfunctional electrolyte and water homeostasis, including peripheral edema, carpal tunnel compression, arthralgia, headache, and myalgia [6,9,10]. Similar side effects to those

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described in acromegalics can also be observed in patients treated with GH [11–15]. These side effects, which can result from GH-induced electrolyte and water retention, often occurs during the initial phase of GHadministration, and a reduction of dose can minimize the symptoms [14,15]. This review is an attempt to explain the renal effects of GH as the result of a combination of both acute and chronic effects. This idea is prompted by our recent finding of an acute effect of GH on the phosphorylation level of the furosemide sensitive kidney specific Na+, K+, 2Cl co-transporter (NKCC2) [16], which may not only play a role during the initial phase of sodium and water retention, but also as a background for later effects seen during chronic GH-exposure. In this review, an acute effect will be defined as occurring within a short time interval (maximally one day) following a bolus injection or the initiation of a constant infusion of a given drug. In general, we consider an acute effect to occur within the first 6 h after injection. Chronic administration of a given drug will refer to continuous administration during several days, either as repeated injections or constant infusion. During chronic administration, compensatory mechanisms may be observed. A compensatory mechanism will be classified as a mechanism that counteracts the direct effect of a drug. However, mechanisms that decrease the plasma concentration of a drug due to normal clearance, and/or metabolic degradation are not considered compensatory.

and circulating IGF-I is found either bound to specific IGF binding proteins (IGFBPs) or in an unbound free form [36,37]. In situ hybridization showed tubular IGF-I mRNA to be predominantly localized in the cortical and medullary collecting duct region [38]. In rats, renal IGF-I mRNA content is increased after chronic GH-treatment [32,39] and the levels of IGF-I mRNA in collecting ducts are increased after incubation with GH [32,39]. Moreover, chronic GH-administration causes a ten-fold increase in IGF-I mRNA in collecting ducts, as compared to whole kidney IGF-I mRNA [39]. Rats receiving a bolus injection of rat (r)GH have an increase in cortical IGF-I mRNA abundance 5 h after rGH-administration, while no difference in IGF-I mRNA content, is found within the medullary portion of the kidney [16]. In rats, immunoreactive IGF-I is localized exclusively to collecting duct principal cells and chronic GH-exposure increases immunoreactive IGF-I only in these cells [32,39]. Additionally, IGF-I production in suspensions of collecting ducts increases after GH-administration in a time- and concentrationdependent manner. The produced IGF-I is released into the surrounding medium and IGF-I isolated from collecting ducts has analogous properties to those of recombinant human IGF-I [40]. Moreover, multiple binding sites for IGF-I is found within the kidney [38,41] and mRNA for the IGF-I receptor is widely distributed in renal epithelia cells [42,43].

2. The renal GH/insulin-like growth factor I (IGF-I) axis

3. Acute effects of GH on electrolyte and water homeostasis

Whole body autoradiography of rats 30 min after infusion of 125I-labelled human (h)GH, shows intense staining of liver and kidneys [17]. Consistently, the GH receptor (GHR) has been localized to the renal tubules. In situ hybridization showed that GHR mRNA was expressed in the proximal tubule, thin descending limb, thick ascending limb, and the collecting duct system in the rat kidney [18]. The results were confirmed by immunohistochemistry, and further it was shown that GHR immunolabelling was strongest in the distal convoluted tubule and collecting ducts [19]. mRNA for the human GHR has also been found in the kidney by several groups [20–22]. The human GHR is distributed throughout most epithelia in the kidney, although in comparison to rodents, the renal medulla showed the strongest immunoreactivity [23]. GH is the main secretagogue of IGF-I, and chronic administration of GH has consistently been shown to increase IGF-I production [4,5,8,13,24–34]. IGF-I is produced in a variety of tissues, and is thought to work in an autocrine/paracrine, as well as in an endocrine, manner. The hepatic biosynthesis seems to account for the largest fraction of the IGF-I in the circulation [35]

Studies in humans have reported an acute decrease in urinary sodium excretion within the first day of GHadministration [44,45]. When two intramuscular bolus injections of GH were given within 4 h to healthy humans, sodium excretion was decreased within the first day, but returned back to baseline on the second day [45]. Conversely, no acute anti-diuretic effect has been reported in humans, within the first day of GH-administration [5,46]. In rats, the acute anti-natriuretic and anti-diuretic effects of GH are more pronounced. Saline loaded rats injected subcutaneously with hGH show a decrease in the urinary sodium excretion and urinary volume within 2 h after injection [2]. Moreover, the anti-natriuretic and anti-diuretic effects are maintained 6 h after injection. The acute reduction in urinary volume was only moderate when the study was repeated in water loaded rats, despite a marked decrease in the urinary excretion of sodium [2], suggesting that sodium reabsorption occurs despite disturbances in the fluid balance. Another study investigated the anti-natriuretic effect of hGH in water loaded rats between 2 h and 15 h after an intraperitoneal bolus injection of GH. Compared to baseline, the uri-

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nary sodium excretion was decreased by 60% in the third hour after the injection, and by 45% in the fifth hour after injection. Sodium excretion was virtually normalized in the ninth hour and in the fourteenth hour after the injection [47]. Additionally, in hypophysectomized rats on a low sodium diet, a decrease in urinary sodium excretion and urinary volume was observed 2 h after a GH-injection [48]. Similar studies in rats [3] and cats [49] has reported equivalent changes during acute GH-administration. Furthermore, rats receiving a bolus injection of rGH had a reduction in urinary volume and sodium excretion after 5 h as well as a reduction in the fractional excretion of both water and sodium, representative of an increased renal sodium and water reabsorption. Moreover, urinary osmolality was also elevated in the experiment, suggesting an increased urinary concentration [16]. In vitro microperfusion of isolated rabbit proximal tubules has shown that neither a physiological nor a pharmacological dose of GH, had an effect on volume absorption [50]. These observations suggest that the anti-diuretic effect of GH is not originating from a direct interaction between GH, and the proximal tubule. Lithium clearance (CLi) is often used as an estimate of proximal tubular transport of sodium and water, hence the fractional excretion of lithium serves as an estimate of the fractional excretion of sodium and water in the proximal tubule (i.e., the percentage of filtered sodium or water that is delivered to tubular segments distal to the proximal tubule) [51–53]. No change in CLi or the fractional excretion of lithium was observed in the first 5 h after injection of rGH in rats, despite the occurrence of marked anti-natriuresis and anti-diuresis [16]. Taken together, these studies indicate that the acute anti-diuretic and anti-natriuretic effects of GH does not rely on changes in proximal tubular reabsorption, but are based on increased water and sodium reabsorption in more distal tubular segments. The urinary potassium excretion is decreased in patients within a day after initiation of GH-administration [44]. Similarly, 5 h after a bolus injection of rGH, a decrease in urinary potassium excretion and fractional excretion of potassium is also observed in rats [16]. Moreover, in rats administered GH for three days, an immediate anti-kaliuretic effect is observed on the first day of GH-administration [54]. Urinary chloride excretion seems to follow sodium in the above experiment [54], and in rats after acute rGH-administration [2,16] . The effect of IGF-I on electrolyte and water reabsorption by the kidney is less well defined. A decrease in sodium excretion was observed after acute administration of IGF-I [55,56], but no change was observed in the urinary volume [56] or the water balance [57]. Infusion of IGF-I for 3 h in humans robustly reduces the plasma potassium concentration after 90 min of

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infusion, while the plasma sodium concentration remains unaffected. However, both the fractional excretion of sodium and potassium were decreased during the last 90 min of infusion [58]. The drop in plasma potassium is likely due to an IGF-I-induced increase in Na– K-ATPase activity in peripheral organs [59]. As with GH, IGF-I does not appear to stimulate proximal tubular water transport, since in vitro microperfusion of rabbit proximal tubules after basolateral addition of IGF-I has no effect on volume absorption [50]. Although, the effects of GH and IGF-I appear to be somewhat similar, they do divert in one important aspect: GH stimulates renal water reabsorption, while IGF-I has apparently no effect on this process. This may suggest that GH and IGF-I stimulates renal electrolyte and water handling through different mechanisms. However, since no studies have investigated the fractional excretion of water in response to acute IGFI administration, it is unknown whether changes in glomerular filtration rate in response to IGF-I (discussed later) may mask a potential anti-diuretic effect of IGF-I.

4. Chronic effects of GH on electrolyte and water homeostasis 4.1. Effects of GH on extracellular volume As mentioned earlier, changes in body fluid homeostasis are seen in several diseases involving dysregulation of GH secretion. Individuals with acromegaly present with a larger than normal amount of total body water (TBW) [6,60], while patients suffering from GHD have a subnormal TBW [7]. Moreover, TBW increases after chronic GH-treatment in patients with GHD [61]. An increase in TBW is also observed in healthy adults during GH-administration [25]. The distorted TBW is largely due to a change in extracellular volume. ECV is lower than normal in GHD patients [7], and increases in patients with GHD [8,27–29] as well as healthy volunteers [13,24,25,62] after chronic GH-administration. Additionally, patients with acromegaly presents with an enlarged ECV [6]. 4.2. Effects of GH on blood pressure The potential effect of GH on blood pressure is poorly understood. In most studies, prolonged administration of GH increases ECV, but not plasma volume (PV) [13,24,25]. Moreover, GH-administration does not alter mean arterial blood pressure in healthy subjects or rodents [5,13,26,46,63–65]. According to the World Health Organization (WHO), 38% of patients with acromegaly have hypertension [66] and most studies report that a higher percentage of acromegalics have hypertension, compared to the normal population [67–69]. In 500

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patients suffering from acromegaly, half of the patients were hypertensive or taking anti-hypertensive drugs, although GH levels were comparable between the normotensive and hypertensive patients [69]. Studies have not been able to directly correlate GH levels with hypertension in acromegalics [69–71], although lowering circulating GH-concentrations significantly reduces blood pressure in these patients [70,72,73]. When GH-hypersecretion was investigated in relation to hypertension in 39 acromegalic patients, with active or cured acromegaly, it was found that hypertension was present in 43% of patients with active acromegaly, and in 28% of patients with cured acromegaly [74]. The hypertensive state associated with acromegaly has been suggested to be determined by the genetic background of the patients, and not the actual disease [66]. However, a study by Vitale et al. evaluated the prevalence of hypertension in 200 acromegalic patients, and 200 non-acromegalic controls. They found that 46% of the acromegalics were hypertensive, whereas only 25% of the controls were hypertensive. Interestingly, only 30% of the hypertensive acromegalic patients had a family history of hypertension, compared to 62% of the hypertensive controls [75]. Moreover, as evaluated by telemetry, transgenic mice overexpressing bovine (b)GH have a higher mean arterial blood pressure than wild type controls [76]. In another study, 24 h ambulatory blood pressure in 25 patients with active acromegaly was monitored. The prevalence of hypertension was between 40% and 56%, and the non-dipper pattern (i.e., failure to sufficiently lower nightly blood pressure) was observed in twelve of the subjects (six hypertensive and six normotensive). The acromegalics with the non-dipper pattern presented with a higher serum GH concentration levels, than patients with a normal dipper pattern [68]. Taken together, these results suggest that even though no direct link can be established between GH and hypertension in acromegaly, reduction of systemic GH levels have profound effects on the blood pressure in this condition. Additionally, a prolonged augmented GH secretion might play a role in the occurrence of the non-dipper pattern. A few studies have used 24 h ambulatory blood measurements to study the effect of GH replacement in patients with GHD, thus allowing for a more sensitive measurement of blood pressure and fluctuations therein. The data presented are not entirely consistent, as the studies indicate that GH administration is followed by either no change in blood pressure [77], an increase in systolic blood pressure after acute GH-administration, but no changes after chronic protocols performed in parallel [78] or a decrease in both systolic and diastolic pressure after 12 months of GH administration [79]. Thus, chronic GH treatment appears not to increase blood pressure in patients with GHD. This conclusion was also reached from a metaanalysis of 10 studies on

the effect of GH treatment in GHD patients [80]. From the analysis, it was concluded that GH treatment reduces diastolic blood pressure in GHD adults. Of particular interest with regard to the role of GH in electrolyte and water homeostasis, the authors note, ‘‘in most studies, mild fluid retention was observed and led to a reduction in the GH dose or withdrawal of patients from the trial’’. One may consider if the inclusion of these patients could have influenced the final outcome of the metaanalysis [80]. The decreased diastolic blood pressure observed in the metaanalysis is likely the result of an augmented IGF-I production due to restoration of GH levels in these individuals. As with GH, chronic IGF-I-administration increases ECV, without altering PV [81]. IGF-I-administration induces a transient drop in blood pressure within the first days of treatment [56,82]. However, no further effects of IGF-I on blood pressure are observed [34,64,65,83]. The IGF-I-induced blood pressure drop may be dose-dependent, as the effect is not consistently observed in all studies. The effect of IGF-I on peripheral resistances appears to occur trough an endothelialdependent mechanism [84] via the stimulated release of nitric oxide (NO) [15,82,85] and increased cGMP coupled signaling [15]. Moreover, pre-treatment with LNG-Nitroarginine methyl ester (L-NAME; a potent non-selective inhibitor of nitric oxide synthases) completely blocks the transient blood pressure drop [82]. The link between GH/IGF-1 and NO release is further supported by a study in adult GHD patients, where impaired production of systemic NO was observed and GH therapy markedly improved NO formation [15]. The GH induced IGF-I dependent vascular relaxation is likely sustained during chronic GH-administration (as exemplified by an augmented glomerular filtration rate (discussed later)). However, the lack of larger fluctuations in blood pressure in these states appears to be compensated out by an increased heart rate and cardiac output [86]. Thus, the effect of GH on blood pressure is the result of a complicated interplay between direct and indirect (through IGF-I) effects of GH on the cardiovascular system and may also involve renal effects. In addition, in studies employing chronic protocols of GH-administration and conditions such as acromegaly, other compensatory mechanisms affecting blood pressure must also be considered in order to describe the effects of GH on blood pressure. 4.3. Effects of GH on urinary electrolyte excretion and urinary volume Chronic GH-administration to healthy humans decreases urinary sodium excretion. This has been observed in a number of studies [4,5,24,28,65]. In several cases, the decreased sodium excretion is transient, only occurring within the first days of GH-administration

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[5,24,28]. After weeks of GH-treatment, the urinary sodium output seems to normalize [28], possibly due to compensatory changes. In contrast, some studies have failed to show any change in urinary sodium excretion during GH administration for 1–2 weeks [25,87]. A likely explanation for this discrepancy can be the doses given during these studies or the individual responsiveness to GH. In normal [88] and Lewis dwarf rats [31], chronic GH-administration also decreases urinary sodium excretion initially, while no change in sodium excretion is observed during prolonged GH-administration (six months) [17]. Moreover, a transient effect can also be observed in rats during chronic GH-administration [54]. Urine volume seems to follow sodium in human trials during chronic GH-administration [4]. Similarly, a transient decrease in urinary volume can be observed during the initial phase of GH-administration [5]. In humans undergoing chronic GH-administration, CLi is either increased or unchanged [4,28]. One study was carried out in ten adult humans with adult-onset hypopituitarism, as a seven day randomized, cross-over trial, followed by twelve months of GH-treatment. The fractional lithium excretion was unchanged after seven days and after twelve months of GH-treatment [28]. The second study investigated the effect of chronic GH-administration to healthy adult humans in a six day randomized cross-over trial. CLi on the sixth day was increased; and the proximal fractional reabsorption of sodium showed a trend towards a decrease [4]. In essence, proximal tubular sodium and water transport is either unchanged or possibly decreased during chronic GH-exposure. Urinary potassium excretion seems to follow the pattern observed for urinary sodium during chronic GHadministration in healthy volunteers [4,24]. In rats, an anti-kaliuretic effect has also been observed during chronic GH-administration [31,88]. Moreover, urinary chloride excretion is decreased in patients chronically treated with GH [44]. Few studies have investigated the effect of chronic GH-administration on urinary osmolality. Transient decreases in the urinary sodium excretion and urinary volume were observed in healthy humans on the third day of GH-administration. However, no change in urinary osmolality was observed at any of the days [5]. Chronic GH-administration does not have any effect on plasma sodium concentration in healthy subjects [4,13,24,25,81,89], GHD patients [27], nor in rats [17,31]. As with the plasma sodium concentration, the plasma potassium concentration is unchanged after chronic GH-treatment in healthy volunteers, GHD patients, and rats [4,13,17,24,25,27,31,89] Moreover, adult acromegalic patients all have plasma potassium within the normal range [90,91]. In humans, undergoing chronic IGF-I-administration, the urinary sodium and potassium excretions are

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transiently decreased [81,92], but unchanged after weeks of treatment [81,87,93], thus following the pattern of GH. In summary, the renal effects of chronic GH exposure seems to be the result of an initial phase of sodium and water retention, and a subsequent phase of re-established sodium and water balance. It remains unknown how much the initial retention of electrolytes and water participates in expanding the ECV and what mechanisms that is responsible for the sustained expansion of the ECV. 4.4. Role of GH in type 1 diabetes mellitus (T1DM) Similarly to acromegalics, patients with T1DM have an increased amplitude and frequency of pulsatile GH peaks [94,95]. Normalization of GH-secretion can be achieved after intense insulin treatment in these patients [96], although patients with well controlled T1DM, still present with diurnal and exercise induced GH-hypersecretion [97,98]. In T1DM, plasma IGF-I levels are found below or in the lower end of the normal range, due to hepatic GH resistance [96]. Likewise, streptozotocin (STZ) induced diabetes in mice has been shown to augment GH secretion and GH resistance, thereby resembling the human condition [99]. Recent studies have raised the possibility that subtle increases in nightly blood pressure (i.e., the ‘‘non-dipper’’ pattern) may play a role in the genesis of microalbuminuria and hence diabetic renal disease [100]. GH plays a possible regulatory role in the circadian blood pressure rhythm [68] and treatment with a GHR antagonist in STZ diabetic mice, blocks increases in albumin excretion and renal/glomerular size and hence the early features of diabetic kidney disease [101]. Although no causal relationship has been presented between the pronounced acute anti-natriuretic and anti-diuretic effects of GH [2,3,16,44,45,47–49] and the prevalence of the non-dipper pattern in diabetes, a better understanding of the renal effects of GH may be clinically important in the prevention of the secondary complications associated with T1DM.

5. GH modulates glomerular filtration rate (GFR) through IGF-I Chronic GH-administration has been shown to increase GFR in healthy adults [26,87,89], while hypophysectomy decreases GFR in patients [102]. Increased GFR is also observed in dwarf rats in response to chronic GH-treatment [31,103], in normal rats [104], and in transgenic mice overexpressing bGH [76]. It is generally accepted that the effect of GH on GFR is due to an increased IGF-I production. Acute infusion of GH has no effect on GFR in humans [46], and rats receiving

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rGH for 5 h show no change in the estimated GFR (creatinine clearance) as well as no change in systemic IGF-I [16]. The GH-induced, IGF-I dependent, stimulation of GFR is best illustrated in a study by Hirschberg et al., where healthy adults received a bolus injection of GH. Plasma GH levels peaked after 2 h, and then began to decrease back towards baseline. Plasma IGF-I did not change during the first 5 1/2 h after GH-injection on the first day, and neither did GFR. By the second day, plasma IGF-I was elevated twofold, plasma GH was back at baseline, and GFR was significantly increased [105]. In contrast to GH, acute effects of IGF-I on GFR have been observed in humans [56] and rats [64,83]. Similarly, chronic treatment with IGF-I is associated with increased GFR in humans [56,106] and rats [34,107,108]. Renal micropuncture and clearance studies have aided in clarifying the mechanisms of the IGF-Idependent rise in GFR. Administration of IGF-I increases single nephron GFR (SNGFR) in rats [34,103,108], and this increase correlates with an increase in renal plasma flow (RPF). Administration of GH or IGF-I to humans [56,58,87] and rats [34,64,82, 83,103,104,108] has been found to increase RPF, whereas hypophysectomy decreases RPF [102]. In the absence of changes in arterial blood pressure, RPF is inversely proportional related to the renal vascular resistance (RVR). IGF-I can transiently decrease arterial blood pressure [56,82], although this mechanism would be expected to impose a reduction in RPF. Therefore, augmentation of RPF following administration of IGF-I must be the result of a decrease in RVR. In fact, reductions in RVR were observed after chronic treatment with GH and IGF-I, as well as acute IGF-I-administration [34,56,58,64,82,83,103,108]. The decreased RVR is due to an IGF-I-induced decrease in both afferent and efferent arteriolar resistances [83,103]. Moreover, since RPF and GFR increased proportionally after GH or IGF-I-treatment, the filtration fraction (FF), the ratio of plasma filtered into the lumen of the renal tubules, remained unchanged [34,58,83,87,103,104]. Studies have also reported that the glomerular ultrafiltration coefficient (LpA) increases in rats after IGF-I-administration [34,103,108]. LpA is defined as the product of the hydraulic conductivity (the volume of water and small solutes that will move through a cross-sectional area perpendicular to the direction of flow), and the glomerular surface area. Since glomerular surface area is unchanged, at least in the acute IGF-I models [108], a change in the hydraulic conductivity appears to be the contributing factor. However, the physiological importance of this mechanism is uncertain since an increase of LpA would be expected to augment FF. The effect of IGF-I on GFR is either partially blocked [82] or completely blocked [83,89], by pretreatment with indomethacin [82,83,89] or L-NAME [82]. This is consistent with an effect of IGF-I on renal arterioles to induce vasodilation

and augment GFR, in part by the same mechanism as that described in Section 4.2.

6. Role of Aquaporin 2, NKCC2 and the Na/K-ATPase in GH induced electrolyte and water retention 6.1. Aquaporin 2 (AQP2) The final concentration of the urine depends on (1) the built up of a medullary osmotic gradient by the loop of Henle and (2) the water permeability of the collecting duct system (see review [109]). An acute decrease in urinary volume [2,3,16,48] and an increase in urinary osmolality [16], observed after a bolus injection of GH to rats could suggest an increased water reabsorption in the collecting duct system, as this is the main site for regulated renal water transport. This is further supported by the observation, that no change in proximal tubular water transport is observed in our 5 h rGH model [16]. However, no change in phosphorylation level or subcellular rearrangement of AQP2 was observed during these experimental conditions [16], suggesting that the anti-diuretic effect observed in rats injected with a bolus of rGH, is independent of increased collecting duct water permeability. Thus, GH may increase water reabsorption by augmenting the osmotic driving force between the collecting duct and descending thin limb lumen, and the interstitium. 6.2. The kidney specific Na, K, 2Cl co-transporter NKCC2 The thick ascending limb (TAL) extends from the inner stripe of outer medulla (ISOM) throughout the cortex. Approximately 25–30% of the filtered NaCl is reabsorbed in this segment. The water permeability of this segment is very low. Thus, NaCl reabsorption in this part of the nephron always serves to dilute the tubular fluid. Moreover, NaCl removal in the TAL serves an important function in regard to water transport, since it decreases osmolality of the luminal fluid and increases interstitial osmolality, allowing more water reabsorption from the collecting duct and the thin descending limb [110]. The TAL can be divided into two regions; the medullary TAL (mTAL) and the cortical TAL (cTAL). The mTAL is primarily responsible for generating a hypertonic interstitium and thereby establishing the osmotic driving force for water removal from the collecting duct and thin descending limbs, while the cTAL chiefly has to remove NaCl from a very dilute tubular fluid [110,111]. In the TAL, sodium is primarily taken up by the furosemide sensitive electroneutral NKCC2 co-transporter (formerly known as BSC1 due to its sensitivity to bumetanide). NKCC2 is located in apical membrane domains of medullary and cortical thick ascending limb cells [112],

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and in the macula densa [113,114]. Here it mediates the inward transport of Na+, K+, and 2Cl. The driving force for NaCl uptake is provided by the basolateral Na–KATPase, which maintains a low intracellular sodium concentration, and thus a steep sodium gradient over the apical plasma membrane [110]. The inward co-transported chloride exits the cell through basolateral located chloride channels while sodium is pumped out by the basolateral Na–K-ATPase. Conversely, potassium transported inward by NKCC2 leaves the cell apically, following its electrochemical gradient through apical K+ channels [111]. This mechanism of cellular transport generates a voltage difference across the epithelium, allowing paracellular transport of cations (such as Ca2+ and Mg2+). Several hormones are known to modulate transport in the TAL, including vasopressin (AVP) [115]. Three phosphorylation sites have been identified in NKCC2 corresponding to three threonines in the N-terminal part

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of NKCC2 [116]. The phosphorylated fraction of NKCC2 has been localized exclusively to apical plasma membranes in the TAL [16] while total NKCC2 is distributed between apically located vesicles and plasma membrane domains. Evidence for the involvement of these phospho-sites in regulating NKCC2 activity, has been provided by Gimenez and Forbush from studies in Xenopus oocytes [116]. The results suggest that these phospho-sites are necessary for increasing the transport rate of NKCC2, when exposed to hypertonic media. Additionally, after acute AVP administration in mice, a significant increase in the phosphorylation of NKCC2 in the inner stripe of mTAL is observed [117]. This is expected to be of significance for the role of NKCC2 in augmenting urinary concentration in response to vasopressin. Rodents maintain a low level of NKCC2 phosphorylation in the medulla, during basal conditions [16,117], suggesting that the normal activity of NKCC2

Fig. 1. Immunohisthochemical analysis of NKCC2 phosphorylation using an anti-phospho-NKCC2 antibody (anti-p-NKCC2). Paraffin-embedded kidney sections from rats receiving a bolus injection of either saline (A, C) or rGH (B, D) were stained with the anti-p-NKCC2 antibody. Pictures from the cortex (A, B) and inner stripe of outer medulla (C, D) were obtained through a 25· objective and the scale bar = 50 lm. GL, glomerulus; cTAL, cortical thick ascending limb; MD, macula densa; DCT, distal convoluted tubule; PT, proximal tubule; mTAL, medullary thick ascending limb; CD, collecting duct; TL, thin limbs. Note a marked increase in mTAL immunostaining in rats receiving GH. The figure adapted from [16] is used with permission.

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in that segment, is enough to maintain its function under normal conditions. Moreover, the inner mTAL region in mice has been shown to have a high sensitivity to AVP, and net reabsorption of NaCl is significantly stimulated by the hormone while the cTAL does not increase NaCl transport in response to AVP [118]. We have recently shown that an increase in NKCC2 phosphorylation occurs in the inner mTAL of rats, 5 h after an rGH-injection [16] (Fig. 1). This increase in phosphorylation coincides with an increased reabsorption of electrolytes and water [16]. These results were not reproducible in isolated microperfused rat mTAL tubuli, as rGH failed to increase transepithelial voltage. However, the results strongly supports that rGH acutely increases electrolyte and water reabsorption by indirectly stimulating NKCC2 via a secondary mediator. Moreover, it is also possible that GH-induced changes in NKCC2 function are not reflected in the transepithelial voltage gradient. Additionally, we found an increase in NKCC2 protein abundance in the cTAL 5 h after a bolus injection of rGH [16]. On the basis of these findings, a theory based on the acute actions of GH and on the regulatory function of the NKCC2 co-transporter, can be proposed (Fig. 2).

Due to the rGH-induced increase in NKCC2 phosphorylation in the mTAL, a greater transport of NaCl into the interstitium can be anticipated. This would explain the increased NaCl reabsorption observed after acute GH-administration. In theory, increased NKCC2 transport would increase the osmotic driving force for medullary water reabsorption both by increasing the interstitial osmolality and by decreasing the osmolality of the filtrate reaching the collecting duct. As no regulation of AQP2 in the collecting duct, and no change in the estimated proximal tubular water reabsorption was found in response to rGH-administration [16], the anti-diuretic effect observed after acute GH-administration so far seem only to depend on the ability of NKCC2 to increase the osmotic driving force for water reabsorption in the collecting duct and descending thin limb segments. In addition, 20% of the filtered K+ is reabsorbed in the TAL during normal conditions [119] and an increase in NKCC2 activity, could help explain the acute antikaliuretic effect of GH [16]. However, although speculative, increased NKCC2 activity would also dilute the urine more before leaving the mTAL, and assuming that AVP and aldosterone is unchanged in this model, one would expect that the uptake of sodium in the collecting

A

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Fig. 2. Schematic drawing showing how acute GH administration increases electrolyte and water reabsorption in the kidney. A: In the mTAL, inward transported NaCl exits the mTAL cells through basolateral chloride channels (CLC-Kb2) or via the Na–K-ATPase, while potassium cotransported with NaCl is recycled over the apical membrane through ROMK, an apical situated potassium channel. A fraction of the inward transported potassium exits the cell over the basolateral membrane, however the mechanism by which this occurs is not entirely clear. In the collecting duct (CD), water is reabsorbed apically through AQP2 and exits basolaterally through Aquaporin 3 and 4 (AQP3–4). Sodium is taken up by ENaC, an apical situated sodium channel, which leads to secretion of potassium trough ROMK in this segment. B: Increased net fluxes of Na+, K+, Cl and water resulting from the increased NKCC2 activity associated with GH induced phosphorylation is indicated by an enlargement of the arrows, while reduced fluxes are indicated by a reduction in arrow size. The increased NaCl entering the interstitium from the mTAL upon GHadministration augments water transport from the descending thin limb (not shown) and the collecting duct, although the osmotic water permeability of the CD may not change. Additionally, a decreased delivery of sodium to the CD may reduce secretion of potassium in the segment.

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duct, is reduced. Consequently, secretion of potassium would be decreased in the collecting duct segment, and less potassium would enter the urine. However, the flow rate of urine in the collecting duct is most likely also affected and thus it is difficult to predict how much collecting duct potassium secretion is reduced, and therefore how much this contributes to the overall potassium reabsorption in this model. Although this mechanism may help to explain the acute effects of GH, the role of NKCC2 in chronic conditions might be more difficult to dissect. As is evident from the literature, GH has a transient effect on renal sodium and water excretion [5,24,28], indicating that during prolonged conditions of GH-administration, the NKCC2 mediated effect is outweighed by compensatory effects. Several speculative scenarios in which GH affects NKCC2 or other important transport proteins during chronic GH-exposure could be suggested. However, since GH has no effect on isolated microperfused mTAL tubuli [16], activation of NKCC2 is most likely mediated by a secondary mediator (based on the lack of effect during these conditions). During prolonged GH-exposure, regulation of this mediator could likely explain the transient effect of GH on renal electrolyte and water transport. Studies utilizing the yeast two hybrid systems, have shown that NKCC2 interacts with two so-called stress activated serine–threonine kinases [120]. One is the Ste20-related proline–alanine–rich kinase (SPAK). Its homologue in rats, the proline–alanine-rich Ste20related kinase (PASK), is expressed in the distal tubules in the kidney [121]. Another closely related kinase, the so-called oxidative stress response 1 (OSR 1) [120], was also identified. Using northern blot analysis, the kinase was shown to be expressed in all organs examined, including the kidney [122]. These kinases both bind to and phosphorylate NKCC2 [123,124]. Moreover, recent data has also shown that the with-no-lysine (K) kinase 3 (WNK3) plays a role in regulating the phosphorylation level of NKCC2 [125]. However, as it seems likely that GH acts through a secondary mediator it remains unclear how phosphorylation and subsequent activation of NKCC2 occurs after GH-administration. Despite these uncertainties the role of these kinases should be investigated in acute and chronic GH models, as they might prove valuable for understanding the mechanisms by which GH modulates renal tubular transport. 6.3. The Na–K-ATPase In the kidney, the Na–K-ATPase provides the main driving force for transepithelial NaCl reabsorption. GH acutely stimulates basolateral Na–K-ATPase activity in isolated canine renal proximal tubule segments under certain conditions [126]. These results are in contrast to other studies showing either no change in rabbit proximal tubular transepithelial voltage or volume

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absorption (which usually are is coupled in this segment of the nephron) after GH-addition [50] or no change in the fractional excretion of lithium 5 h after rGH administration in rats, both indicating no changes in proximal tubular Na–K-ATPase activity [16]. Chronic studies in acromegalics [127] and rats [128] have suggested that increased activity of the Na–KATPase plays a role for the effects of GH on electrolyte and water homeostasis. However, other studies report no effect of GH on Na–K-ATPase abundance, or even a decreased activity of the Na–K-ATPase [129,130]. During chronic GH-exposure, Na–K-ATPase abundance increases in rat muscle, after treatment with hGH for 16 days [131]. However, when hypophysectomized rats were administered GH for 11 days, no increase in Na–K-ATPase activity was observed [129]. Another study investigated the activity of the Na–KATPase after seven days of treatment in rats, and found that GH greatly increased the activity of the Na–KATPase in liver, kidney and brain [128]. The discrepancy between the studies might be dependant on the GH-stimulated increase in insulin and/or IGF-I levels, which have been shown to stimulate Na– K-ATPase activity [59,132–135]. Thus, a direct stimulation of the Na–K-ATPase by GH seems unlikely, at least in the acute setting, when systemic IGF-I and insulin remains unaltered [16]. However as both IGF-I and insulin are expected to increase in response to chronic GH stimulation, a role for the Na–K-ATPase in augmenting ECV during these conditions is plausible.

7. GH increases plasma bicarbonate and urinary acidification A few studies have investigated the effects of chronic GH administration on renal acid/base regulation. Serum bicarbonate concentrations are lower in patients with GHD, than in patients with short stature due to other causes. Additionally, chronic GH-treatment increases serum bicarbonate in these patients [136]. Likewise, chronic GH-administration in humans with NH4Cl induced chronic metabolic acidosis also increases plasma bicarbonate concentration. The mechanism appears to result from an increase in net acid excretion, in the presence of an increased renal sodium reabsorption [137]. Acute effects of growth hormone on renal acid/base regulation have also been documented. Experiments on in vitro perfused kidneys from hypophysectomized rats showed these to have a lower H+ secretion, primarily due to lower bicarbonate reabsorption, compared to kidneys from intact animals [138]. Moreover, administration of GH in perfused kidneys from normal and hypophysectomized rats significantly increases acid-excretion, mainly due to enhanced bicarbonate reabsorption, and only with a minor increase in NHþ 4 excretion [138]. The enhanced

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NH+ secretion was not reproducible in rats treated with IGF-I [138]. In vivo experiments on hypophysectomized rats showed increased bicarbonate reabsorption and NHþ 4 excretion in GH-treated rats [138]. The effect does not appear to occur by a direct interaction of GH or IGF-I in the proximal tubules, as GH and IGF-I does not stimulate bicarbonate transport in perfused proximal tubules [50]. Moreover, five hours after rGH-injection, a significant increase in blood bicarbonate concentrations is observed in rats (Dimke et al., unpublished). This occurred in conjunction with an increase in NKCC2 phosphorylation and presumably an increased transport activity of NKCC2 [16]. A tempting interpretation of the data could be that the increased bicarbonate reabsorption occurs in the mTAL and possibly involves increased transcellular NH4+ transport initiated by increased NKCC2 activity [139], although additional studies are needed to fully clarify this issue. The changes in acid–base homeostasis during prolonged GH-administration are unlike the changes observed for the urinary sodium excretion, where a transient effect is observed. GH-administration acutely affects whole body acid/base status in the alkaline direction through a renal mechanism and the GH induced shift in acid/base status is maintained during chronic GH-administration.

8. Interactions between the GH/IGF-I axis and renotrophic hormones Since GH (and IGF-I) fail to stimulate transepithelial voltage in isolated microperfused mTAL tubuli, the acute effect of rGH on NKCC2 phosphorylation appears to be indirect [16]. These results indicate (1) that there is a least one secondary mediator involved and (2) that these secondary mediators do not appear to act in an autocrine manner. It is therefore possible, that other hormones that affect renal tubular transport mediate the acute effects of GH on renal function. This section will review the possible role of hormones with renal effects, which has been shown to be altered in acute or chronic states of GH-exposure, as mediators of the effects seen after GH administration. 8.1. The renin–angiotensin–aldosterone (RAA) system Much effort has been put into clarifying the role of the RAA system in the anti-natriuretic effect observed after GH administration. As changes in components in this system will yield specific renal effects, they could mediate the effects induced by GH. 8.1.1. Renin Chronic GH-treatment has been shown to increase plasma renin activity (PRA) in healthy subjects and GHD patients [4,5,8,24,28]. Contrarily, other studies showed no change in PRA after chronic GH-administra-

tion [14,30,61]. The effects of chronic GH-exposure on PRA are similar in rats, as PRA is either increased or unchanged [17,31,63,140]. Only one study has investigated the acute effect of GH on PRA in humans. They observe no changes in PRA between 30 min and 240 min after a bolus injection of GH [141]. The acute effect of GH on PRA and renin release has been studied more thoroughly in rodents. Hypophysectomized rats did not show any change in PRA 24 h after a bolus injection of GH. The kidneys from these rats had a renin content similar to that of kidneys from untreated animals, but secreted renin at a much higher rate [140]. Still, isolated mouse juxtaglomerular cells incubated with GH, showed no change in renin secretion [63]. No good explanation has been presented for the discrepancy between these studies. 8.1.2. Angiotensin II The effect of GH on angiotensin II (Ang II) is just as puzzling as the effects of GH on PRA, which is to be expected since the amount of Ang II is dependant on PRA. The Ang II concentration has been found to be either increased or unchanged in humans after chronic GH-treatment [13,24,28,61]. Moreover, GH-treatment increases Ang II receptor densities in the kidney of dwarf rats [31]. In our recent study of the acute renal effects of GH, the estimated GFR (by creatinine clearance) was unchanged [16]. If PRA and hence Ang II was increased in this setting, a decreased filtration rate (albeit with increased filtered fraction) would have been expected, due to the effects of Ang II on the afferent and efferent arterioles [142–144]. Moreover, we observed no change in the fractional excretion of lithium and consequently no change in proximal tubular sodium reabsorption [16]. If Ang II was increased in this model, that would have been expected to be reflected in the fractional excretion of lithium [142,144]. 8.1.3. Aldosterone Plasma aldosterone is either reported to increase [4,5,13,24] or remain unchanged [14,28,31,145], after GH-treatment in humans and rats. However, adrenalectomized rats receiving GH-treatment for three days show an immediate decrease in sodium excretion, in the same manner as normal rats [54]. Moreover, a bilaterally adrenalectomized patient showed GH-induced sodium retention within 24 h after GH-administration [45]. It therefore seems unlikely, that either the acute and chronic effects of GH are mediated through aldosterone, although modification of aldosterone levels may be involved in the compensatory changes during long term GH-treatment. 8.2. Vasopressin GH-treatment for five or fourteen days does not change systemic AVP concentrations in healthy adults

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[5,13]. Moreover, chronic GH-administration in children with GHD showed no change in urinary cAMP levels [146,147]. Taken together, these results suggest that GH-administration during chronic conditions stimulates renal transport mechanisms independent of AVP. The same appears to be the case in the acute setting. In one study, a patient with diabetes insipidus showed the same acute anti-natriuretic and anti-kaliuretic response as normal controls, when given a bolus GHinjection [45]. Five hours after rGH-administration to rats, the relative abundance of Ser256-phosphorylated AQP2 as well as the apical abundance of AQP2 were found to be unchanged [16]. As phosphorylation of Ser256 and changes in subcellular distribution of AQP2 is a hallmark of vasopressin action [109,148–153], this also serves as an indirect measure, suggesting that vasopressin is unaltered during acute GH-administration [16]. 8.3. Insulin Insulin may be involved in the anti-natriuretic effects of GH, since GH decreases insulin sensitivity and therefore increases insulin levels [154]. Insulin has a direct effect on the peripheral and renal Na–K-ATPase [59,133], and on chloride flux in the TAL (which is highly dependant on NKCC2 ability to inwardly transport Cl) [155]. It is generally accepted that long term treatment with GH increases insulin levels, and in some human trials insulin levels rise after chronic GH-treatment [4,13,24– 26,28,30]. However, not all studies reports a change in insulin levels under similar conditions, or only a transient rise in insulin levels [27–30,89]. In acromegalics, diurnal insulin is increased, possibly due to prolonged GH-exposure [156]. Although no causal relationship has been presented between augmentation of insulin secretion by chronic GH-administration and electrolyte retention, insulin stimulated Na–K-ATPase activity could be envisioned to contribute to expanding ECV during these conditions. In the acute models, no change in serum insulin is observed five hours after a bolus injection of rGH in rats, although the anti-diuretic and anti-natriuretic effects of GH are evident and an increased phosphorylation of medullary NKCC2 is observed [16]. Critical proof for an insulin independent acute effect of GH was provided from partly pancreatectomized diabetic rats, which after GH administration still showed a significant reduction in urinary sodium and potassium excretion [157]. Blood glucose increases somewhat proportionally to plasma insulin during chronic GH-exposure, largely due to the decrease in insulin sensitivity induced by GH [28,29,89] and possibly by modulation of glycogenolysis [158]. Hyperglycaemia has been shown to stimu-

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late proximal tubular sodium reabsorption in rats, as measured by microperfusion [159]. However, no increase in lithium reabsorption have been reported in humans chronically administered GH [4,28] or in rats receiving a bolus injection of rGH [16], suggesting that proximal tubular sodium reabsorption remains unaffected during these conditions of GH-administration. Glucagon is either decreased or unchanged after GHtreatment, probably in response to insulin and/or glucose levels [26,89]. 8.4. Natriuretic factors Atrial natriuretic peptide (ANP) is released from the atria in response to wall stretch. ANP has been shown to induce a natriuretic response when infused into rats [160,161], however, the exact function of ANP still remains uncertain. ANP acutely promotes water and sodium excretion, whereas the sub-chronic effects involve water retention in rats [161]. A drop in ANP could be a mechanism by which GH induces its antinatriuretic effects. However, no studies have investigated the systemic ANP levels in acute GH models. Chronic GH-administration studies remains contradictory as ANP is found to be unchanged [4,24], decreased [13], or show a trend towards a decrease [28]. In patients with active acromegaly, circulating GH levels are increased while systemic ANP remains unchanged, when compared to patients with inactive acromegaly [162]. In a single study, brain natriuretic peptide was found to be decreased during chronic GHadministration [28].

9. Summary and conclusions The mechanisms underlying the effects of GH on renal electrolyte and water reabsorption have long remained elusive. From this review it is clear, that when studying the effect of GH on renal function, it is important to distinguish between direct and indirect effects of GH as well as between effects observed acutely or chronically after GH administration. In our recent study in rats we have documented the renal response to acute GH-administration in detail and showed that rGH indirectly increases phosphorylation of NKCC2. This may explain the acute effects previously described following GH administration. As shown in this review, there seems to be a general gap in the knowledge on the signaling mechanisms downstream to GH, since the renal effects observed after systemic application of GH does not seem to be mediated by known secondary mediators or hormone systems. Hopefully, further research within this field will be able to identify the secondary mediator(s) responsible for the observed renal effects and possibly document further roles of GH in the kidney.

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Acknowledgements The authors thank Dr. Ju¨rgen Schnermann for helpful comments on the manuscript.

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