Direct renin inhibitor aliskiren increases AQP2 expression in renal collecting ducts and improves urinary concentration defect in NDI

AIM: The direct renin inhibitor aliskiren displays antihypertensive and antialbuminuric effects in humans and in animal models.Emerging evidence has shown that aliskiren localizes and persists in medullary collecting ducts even after treatment was discontinued.The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression and improves urinary concentrating defect induced by lithium. METHODS: The mice were either fed with normal chow or Li Cl diet(40 mmol / kg dry food per day for first 4 days and 20 mmol / kg dry food per day for last 3 days) for seven days. Some mice were intraperitoneally injected aliskiren(50 mg/kg BW per day in saline). RESULTS: Mice injected aliskiren developed decreased urine output and increased urine osmolality when compared with controls. Aliskiren significantly increased protein abundance of AQP2 and phosphorylated-S256 AQP2 in the kidney inner medulla. Immunohistochemistry and immunofluoresence showed increased apical and intracellular labeling of AQP2 and p S256-AQP2 in collecting duct principal cells of kidneys in mice treated with aliskiren. Aliskiren treatment prevented urinary concentrating defect in lithium-treated mice,and improved the downregulation of AQP2 and p S256-AQP2 protein abundance in inner medulla of the kidney. In primary cultured rat inner medulla collecting duct cells,aliskiren dramatically increased AQP2 protein abundance which was significantly inhibited either by PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL12330,indicating an involvement of the c AMP signalling pathway in mediating aliskiren-induced increased AQP2 expression. CONCLUSION: The direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus( NDI) likely via PKA-c AMP pathways.     

Effect of papillary exposure on intrarenal distribution of glomerular filtration rate and of plasma flow

Removal of the renal pelvis in order to expose the renal papilla has been shown to cause impairment of the renal concentrating ability by an unknown mechanism. To study this phenomenon, urine osmolality (Uosm), single-nephron glomerular filtration rate (SNGFR) in outer and inner cortical nephrons and the inner and outer medullary plasma flow were determined. Measurements were performed on groups of rats before (control) and 15, 45 and 90 min after exposure of the left renal papilla. Rats with an intact ureter were studied in parallel to see whether the variables varied within the 90-min period of the study. In all groups of animals with an exposed papilla, Uosm was lower than in non-exposed animals. Outer cortical SNGFR in rats with exposed papillae, regardless of time, was not different from that in control rats. Inner cortical SNGFR after 45 and 90 min of exposure did not differ from that in controls, but after 15 min of exposure it was lower than in control animals. Outer and inner medullary plasma flow did not differ between rats with exposed papillae and controls, irrespective of exposure time. In conclusion, papillary exposure results in a permanent decrease in urine osmolality. This impairment of the concentrating ability cannot be attributed to prolonged changes in renal haemodynamics.     

AQP3 缺失小鼠尿素和尿浓缩能力的研究

目的： 肾脏表达水通道蛋白3（AQP3）在尿浓缩机制中起着极其重要的作用。AQP3缺失小鼠表现为尿浓缩功能严重障碍。为阐明这种基因缺失的生理特性和发生机制,我们利用AQP3基因敲除小鼠和野生型小鼠复制急性尿素负荷动物模型,对其作用机制及影响进行研究。方法: 对小鼠实施急性尿素负荷,从实验前2 h到尿素负荷后第8 h,每隔2 h收集1次尿样分别检测尿量、尿渗透压及尿素浓度。分离肾脏组织RNA进行实时荧光定量RT-PCR反应。应用Western blotting分析肾组织中尿素转运蛋白（UTs）的变化。结果: 给予尿素后4 h左右,2种不同基因型小鼠均有负荷尿素的排泄。尿素负荷后AQP3缺失小鼠尿的渗透压和尿素含量逐渐增高,第 8 h,几乎与野生型小鼠值相等,但尿中非尿素溶质浓度却没有改变。在最后4 h内尿量下降到基础值的1/4。AQP3基因缺失和野生型小鼠尿素负荷显著地上调了UT-A3的表达。结论: AQP3基因缺失并没有直接干扰肾脏对尿素的浓缩功能,但却减弱了对尿中其它溶质浓缩的能力。这种对溶质选择性的反应是由于AQP3对水和尿素转运能力的不同所致。结果表明AQP3对尿中非尿素溶质的浓缩具有特殊作用。     

Influence of lysine-vasopressin dosage on the time course of changes in renal tissue and urinary composition in the conscious rat

1. The changes in urinary and renal tissue composition induced by continuous, intravenous infusion of lysine-vasopressin (2.5, 5, 15 and 60 mu-u./min. 100 g body wt.) for up to 4(1/2) hr in water-loaded, conscious rats were determined.2. Both the magnitude of, and the time required to attain, maximal and stable responses, in respect to both urinary and tissue composition, varied with the dose.3. The dose-dependent changes in medullary composition were compounded of graded decreases in water content and graded increases in solute (mainly Na and urea) content.4. The relative contribution of the changes in water, Na and urea contents varied with time and with dose. Significant increases in papillary urea content occurred with all doses. The range of change in urea content was wider than that for any other solute.5. At low doses, the changes in urinary flow and osmolality were ascribable, almost entirely, to large decreases in free-water clearance, with minor changes in medullary composition; at higher doses, the increases in urinary osmolality were accompanied by steep increases in medullary solute concentrations.6. A variable, dose-dependent, transient natriuresis occurred during the phase of increasing medullary Na concentration; the peak natriuresis preceded the times of maximal osmolal and Na concentrations in the papilla and urine.7. The differences in osmolal, urea and Na concentrations between papilla and urine also changed with time.8. Both the transitional and steady-state changes induced by lysine-vasopressin are discussed in terms of intrarenal mechanisms. It is concluded that the data are most reasonably interpreted on the basis that several hormone-sensitive loci exist in the kidneys, each with individual dose-response and kinetic characteristics.     

Effects of renal lymphatic occlusion and venous constriction on renal function.

The effects of renal lymphatic occlusion or increased lymph flow due to renal vein constriction on renal function were investigated in rats. In each experiment, the renal lymphatics or vein of the left kidney were occluded or constricted and the right kidney served as a control. Occlusion of renal lymphatics caused renal enlargement, no change in glomerular filtration rate, a marked increase in urine flow and solute excretion without any change in urine osmolality, and enhanced urinary loss of urea, potassium, sodium and ammonium. Urea concentrations in medullary and papillary tissues were significantly elevated. Renal vein constriction caused renal enlargement and a marked drop in glomerular filtration rate, urine volume, urine osmolality and solute excretion. tissue concentrations of urea and potassium were decreased in the medulla and papilla and total tissue solute was significantly decreased in the papilla. The data indicate that in the rat, renal lymphatic occlusion traps urea in the medulla and induces a urea diuresis resulting in a large flow of normally concentrated urine. On the other hand, increased lymph flow secondary to renal vein constriction decreases medullary urea and potassium concentrations and papillary osmolality. These changes and the reduced glomerular filtration rate result in a small flow if dilute urine. Thus both renal lymphatic occlusion and enhanced lymph flow have a significant effect on renal function.     

Proximal tubular function in adult rats treated neonatally with enalapril

Neonatal treatment with angiotensin-converting enzyme (ACE) inhibitors or the angiotensin II type-1 receptor antagonist losartan in rats induces irreversible renal histological abnormalities, mainly papillary atrophy, in association with an impairment in urinary concentrating ability. The aim of the present study was to assess proximal tubular function in adult rats treated neonatally with enalapril. Male Wistar rats received daily, intraperitoneal injections of either enalapril (10 mg kg^?1) or isotonic saline vehicle from 3 to 24 days of age. In 15-week-old, hydropenic rats we analysed: (i) proximal tubular iso-osmotic fluid reabsorption using the method of lithium clearance; and (ii) maximal tubular D -glucose reabsorption (Tm_G), under pentobarbital anaesthesia. The main findings were that neonatally enalapril-treated rats showed: (i) reductions in absolute (APRH₂O) and fractional (FPRH₂O) iso-osmotic fluid reabsorption in the proximal tubules (APRH₂O: 0.50 ± 0.02 vs. 0.64 ± 0.03 mL min^?1 g KW^?1, P < 0.05; FPRH₂O: 58 ± 3 vs. 68 ± 2%, P < 0.05); and (ii) a normal Tm_G. In addition, during baseline clearance measurements neonatally enalapril-treated rats showed increases in urine volume and fractional excretion rates of sodium and potassium, a reduction in urine osmolality, whereas glomerular filtration rate and effective renal plasma flow were unaltered. These results suggest that neonatal ACE inhibition produces an irreversible, but differentiated, abnormality in proximal tubular function. Thus, the development of a normal proximal tubular function in the rat seems to be dependent on an intact renin-angiotensin system, (RAS) neonatally.     

Influence of prehydration on the changes in renal tissue composition induced by water diuresis in the rat

1. The composition of renal tissue was determined in rats before and immediately after intravenous infusion of dextrose (2.5 g/100 ml.) in amounts sufficient to administer a positive fluid load of 4% body weight over 2 hr. The rats were classified into three groups, according to the preinfusion urine osmolality: hydropaenia, normal and moderately diuretic (over 2400, 800-1500 and below 800 mu-osmoles/g H(2)O, respectively).2. In non-infused rats, the steepness of the corticomedullary osmolal gradient varied, due to differences in both water and solute (sodium and urea) contents, and was related to urinary osmolality. Whereas differences in medullary and papillary solute contents occurred between all three groups, papillary water content was significantly higher only in the moderately diuretic animals.3. Dextrose infusion caused the induction of water diuresis, the lowest urinary osmolalities being produced in the previously moderately diuretic animals.4. Dextrose infusion caused a considerable reduction in the steepness of the corticomedullary osmolal gradient in all rats, particularly in the previously hydropaenic animals, due to changes in both solute (sodium and urea) and water contents. Whereas reductions in medullary and papillary solute contents occurred in all three groups, there was no further increase in papillary water content from the already high values seen in the noninfused diuretic animals.5. Thus, dextrose infusion largely abolished any previous differences in tissue water content, whereas significant, though small, differences in osmolal (particularly urea) content persisted.6. These data are discussed in terms of changes and differences in endogenous antidiuretic hormone (A.D.H.) release.7. Changes in the magnitude and direction of the urinary-papillary urea concentration difference are discussed in terms of passive transport, with probable A.D.H.-induced changes in nephron urea permeability.     

Irreversible damage to the medullary interstitium in experimental analgesic nephropathy in F344 rats

Renal papillary necrosis (RPN) and a decreased urinary concentrating ability developed during continuous long-term treatment with aspirin and paracetamol in female Fischer 344 rats. Renal structure and concentrating ability were examined after a recovery period of up to 18 weeks, when no analgesics were given, to investigate whether the analgesic-induced changes were reversible. There was no evidence of repair to the damaged medullary interstitial matrix, or proliferation of remaining undamaged type 1 medullary interstitial cells after the recovery period following analgesic treatment. The recovery of urinary concentrating ability was related to the length of analgesic treatment and the extent of the resulting inner medullary structural damage. During the early stages of analgesic treatment, the changes in urinary concentrating ability were reversible, but after prolonged analgesic treatment, maximum urinary concentrating ability failed to recover. This study shows that prolonged analgesic treatment in Fischer 344 rats causes progressive and irreversible damage to the interstitial matrix and type 1 interstitial cells leading to RPN. The associated urinary concentrating defect is reversible only during the early stages of structural damage to the inner medulla.     

Influence of variations in hydration and in solute excretion on the effects of lysine-vasopressin infusion on urinary and renal tissue composition in the conscious rat

1. The changes in urinary and renal tissue composition induced by continuous, intravenous infusion of lysine-vasopressin (60 mu-u./min. 100 g body wt. until steady-state conditions prevailed) in normally hydrated, hydropaenic, saline-loaded (0.9%, w/v) and mannitol-loaded (15%, w/v) rats were determined and compared with those induced in water-loaded rats.2. Previous reports that the urinary responses to antidiuretic hormones vary both with hydration status and with concurrent solute excretion rate were confirmed.3. The data show that variations in urinary responses were accompanied by differences in the papillary responses to lysine-vasopressin.4. The results are discussed in terms of the effects of hydration and concurrent solute excretion on factors influencing (a) medullary accumulation of water and solute, (b) osmotic water reabsorption and (c) osmotic equilibration across the collecting duct; and of the effects of lysine-vasopressin on these factors.5. It is concluded that the effects of hydration and solute excretion on the antidiuretic responses to lysine-vasopressin may be interpreted by differences in (a) the medullary composition prevailing at the start and (b) any further changes in medullary composition that can be induced under the experimental circumstances.     

Analgesic nephropathy in Fischer 344 rats: comparative effects of chronic treatment with either aspirin or paracetamol.

This study has compared the relative nephrotoxicity of chronic treatment with aspirin or paracetamol in an animal model. Changes in renal structure and urinary concentrating ability were examined in female Fischer 344 rats after continuous treatment with either aspirin (120-230 mg/kg body wt/day), or paracetamol (140-210 mg/kg body wt/day), and were compared with age-matched untreated control rats. Renal morphological changes were examined after 40-83 weeks of analgesic treatment, using light and electron microscopy. Aspirin caused renal papillary necrosis and a decrease in urinary concentrating ability, whereas paracetamol alone did not cause significant renal damage. Aspirin produced damage to the interstitial cells and matrix, particularly in the mid-papillary region, followed by changes to the thin limbs of the loop of Henle and medullary capillary endothelium. These structural changes were similar to those described previously, when continuous treatment with combined aspirin and paracetamol was studied in the same animal model.     

Urea reabsorption in the medullary collecting duct of protein-depleted young rats before and after urea infusion

The aims of the present study were to examine urea handling along the length of the medullary collecting duct (MCD) in protein-depleted young rats and to determine the effect of urea infusion on MCD function and urine concentrating ability. In 10 young rats on a low protein diet, urea reabsorption equivalent to 18.3% of the filtered load was observed along the MCD (4.5 mm) using the microcatheterization technique. Collecting duct urea reabsorption occurred almost entirely (16.6%) in the distal portion of the MCD (mid-zone to papillary tip, 2.8 mm). These results are in contrast to the lack of net urea reabsorption along the MCD in protein-replete adult rats [21]. After urea infusion which raised plasma urea level from 3.5 to 10.5 mmol/l in protein-depleted rats, urine non-urea solute concentration increased in the non-exposed right kidney from 827 to 1,199 mosm kg^–1 (P<0.001) but the increase was not significant in the experimental left kidney (590 to 619 mosm kg^–1). Thus exposure of the papilla interfered with urea-induced enhancement of urine concentrating ability. After urea infusion, fractional urea reabsorption in the distal portion of the MCD was similar to that before infusion (21.1%) of filtered load) but the absolute load of urea delivered to the MCD and reabsorbed along the duct was markedly increased (2.7-fold). In 6 rats with an increase in urine non-urea solute concentration in the experimental kidney after urea infusion, fluid reabsorption along the duct was significantly increased. The results indicate that in protein-depleted young rats (1) there is significant urea reabsorption in the distal portion of the medullary collecting duct, (2) urea infusion contributes to enhanced urine concentrating ability, in part, by increasing absolute urea reabsorption and also water reabsorption in the collecting duct.     

Renal medullary hexosamine content following antidiuresis and water-loading in the rat

The effect of antiserum raised against rat urinary (renal) hyaluronidase has been examined in rats subjected to antidiuretic stimuli (water-deprivation or vasopressin infusion). Prior administration of antiserum abolishes the reduction in medullary and papillary extractable hexosamine which normally accompanies antidiuresis. Antiserum against rat testicular hyaluronidase was found to be without effect during water-deprivation. Water-loading significantly increased the level of extractable hexosamine. The findings are considered in relation to previous observations on the effects of antisera on renal and urinary composition and collecting duct morphology under identical experimental conditions. It is suggested that a functional relationship exists between the net degradation of medullary mucopolysaccharides by hyaluronidase and the concentrating capacity of the kidney.     

Pelvic urine composition as a determinant of inner medullary solute concentration and urine osmolarity

Summary To clarify the question whether solute and water fluxes between pelvic urine and the renal papilla contribute to the medullary accumulation of osmotically active substances and thus to final urine concentration, we measured the osmolarity of urine samples from the papillary tip of rat kidneys during superfusion of the exposed papillae with solutions of widely varying osmotic concentrations. When the osmolarity of the superfusion fluid consisted half of urea and half of sodium chloride, urine osmolarity was observed to change parallel to the bath solution over a certain concentration range (800–2000 mosm/l). The changes of urine concentration occurred within 90 min after the start of the papillary superfusion. Similar results were obtained when the sodium chloride concentration was kept constant at 300 mosm/l and the urea concentration varied to yield bath concentrations up to 3000 mosm/l. A rise of urine concentration by papillary superfusion above 2000 mosm/l was achieved when exogenous arginine-vasopressin was infused intravenously suggesting that the failure of urine concentration to equilibrate with the bath concentration was due to a limited water permeability of the collecting ducts. These results suggest that solute and water fluxes between pelvic urine and the renal papilla are a necessary prerequisite to achieve maximal osmotic urine concentrations. In addition, such fluxes may explain the variability of medullary tissue concentrations under various diuretic states.This work was supported by the Deutsche Forschungsgemeinschaft     

Water removal and solute additions determining increases in renal medullary osmolality

Osmolality and solute concentrations of the mammalian renal medulla increase and decrease with changing urine osmolality. These changes are brought about by addition or removal of solute or water to or from the renal medullary tissue. In Munich-Wistar rats and Syrian hamsters, males and females, actual amounts of and the various solutes involved in these changes were determined. Kidneys were removed from animals killed in different stages of water diuresis and antidiuresis. The renal medulla was analyzed by a new method that permits determination of water and solutes on the same piece of tissue. Removal of water and addition of urea were the two most important factors in raising inner medullary osmolality. Papillary water content was inversely related to the papillary osmolality and was 50% lower in extreme antidiuresis compared with water diuresis. Rats had higher papillary water content than hamsters. In the outer medulla, water removal was significant in the hamsters but not in the rats. Addition of urea to the papillary tissue exceeded the osmotic equivalent of NaCl by a factor of 2.8 in both rats and hamsters. Females of both species showed greater changes than males in amounts of urea in the inner medulla.     

Urea handling by the medullary collecting duct of the rat kidney during hydropenia and urea infusion

Previous micropuncture studies of distal tubule fluid and ureteral urine have indicated a varying degree of urea reabsorption in the collecting duct. In the present experiments the microcatheterization technique was used to directly determine urea, Na, K, total solute and fluid reabsorption along the length of the medullary collecting duct in anaesthetized hydropenic rats and in rats given low dose urea infusion (P_urea 18.9 mM/l). In hydropenic rats, the remaining fraction of filtered urea did not change significantly along the collecting duct, as indicated both by regression analysis of all samples and by comparison of paired samples from the corticomedullary junction and papillary tip. During low dose urea infusion, urine osmolality increased in proportion to the increase in urea concentration and again there was no net urea reabsorption between the beginning and end of the duct. However, during urea infusion, analysis of samples from the beginning, mid-zone, and end of the collecting duct indicated that urea entry occurred in the proximal portion of the duct (beginning to mid-zone,P<0.01) and that urea reabsorption occurred in the distal portion (mid-zone to end,P<0.01). The lack of significant net urea reabsorption along the duct despite the excretion of moderately concentrated urine, has implicatios for the concept of medullary urea recycling and for models of the urinary concentrating mechanism. The finding of functional heterogeneity with respect to urea handling in the collecting duct in vivo, with both reabsorption and secretion being demonstrated, raises the possibility that internal recycling of urea in the medullary collecting duct itself may contribute to maintenance of a high papillary interstitial urea concentration.     

心肌梗塞致心力衰竭大鼠模型不同时期尿液水通道蛋白-2的改变

目的:探讨心肌梗塞致心力衰竭大鼠模型不同时期尿液水通道蛋白-2(AQP2)浓度的改变及其与低钠血症的关系。方法:应用左冠状动脉结扎复制慢性心力衰竭大鼠模型,对该模型术后不同时期的大鼠应用Western蛋白印迹测定尿液AQP2浓度并测定24h尿量、血钠、尿渗量等指标。结果:在左冠状动脉结扎术后心力衰竭大鼠模型,尿液AQP2浓度变化有两个峰,一是在术后3d,二是在术后第9周;不同时期心力衰竭组的血钠,尿渗量与对照组比较均存在显著差异。术后第9周心肌梗塞心衰组尿液AQP2光密度值(365%±103%)明显高于心肌梗塞心功能代偿组(179%±81%)及对照组(99%±48%)(P＜0.01)。结论:左冠状动脉结扎术后不同时期心衰大鼠尿液AQP2变化的规律反映了AQP2基因在心力衰竭进程中表达明显增高,肾脏AQP2基因表达增高是心力衰竭伴低钠血症的重要发病原因。     

Impaired urinary concentrating ability and cyclic AMP in K+-depleted rat kidney.

The possibility that an alteration of the vasopressin-dependent cyclic AMP system plays a pathogenic role in the urinary concentrating defect in K+ depletion was investigated in the rat. The antidiuretic response to vasopressin was significantly less in K+-depleted rats. In these K+-depleted rats, the increase in urinary cyclic AMP excretion in response to vasopressin was also significantly less. However, repletion of K+ for 1 wk by feeding high-K+ diets restored the ability to increase urinary cyclic AMP excretion in response to vasopressin. In the in vitro incubation of renal medullary slices, the increase in cyclic AMP concentration in response to vasopressin was also significantly less in the slices obtained from K+-depleted rats than in those obtained from control rats. These findings suggest that, in K+ depletion, there is a reversible impairment of the vasopressin-dependent cyclic AMP system in the renal medulla; this impairment may play a pathogenic role in the urinary concentrating defect in K+ depletion.     

Renal ischaemia/reperfusion injury: possible role of aquaporins

Renal ischaemia/reperfusion (I/R) injury is a common problem that occurs when blood flow is interrupted to the kidney in case of kidney transplantation, aortic cross-clamping and shock with subsequent resuscitation. Renal I/R injury is a complex conditions which includes the onset of an inflammatory process, which is associated with impairment of concentrating ability of the kidney and impairment of solute transport. Characteristically, renal I/R injury is associated with marked reduction in the protein expression of renal aquaporins (AQPs) mainly (AQP1, AQP2 and AQP3), and solute transporters were observed in this condition and could account for the impaired urinary concentration that observed in this condition. Recently, many agents were tested for a possible protective effect against this insult such as erythropoietin (EPO), α-melanocyte-stimulating hormone (α-MSH) and α-lipoic acid which were proved to prevent downregulation of AQPs and solute transporters. The aim of this short review is to outline the potential pathophysiological role of AQPs in renal I/R injury and to put a spotlight on the modulation of renal functions impairment in renal ischaemia by new drugs that prevent downregulation of AQPs.     

Renal cortical accumulation of hyaluronan in adult rats exposed neonatally to angiotensin-converting enzyme inhibition.

Neonatal inhibition of the renin-angiotensin system [angiotensin-converting enzyme (ACE) inhibition] in the rat results in long-term abnormal renal morphology and function, including interstitial inflammation and fibrosis. Hyaluronan (hyaluronic acid, HA) has pathological implications in inflammatory diseases and renal ischaemia-reperfusion injury. The present study aimed at determining if renal cortical HA in the adult rat is correlated to the abnormal morphology and function in rats treated neonatally with the ACE inhibitor enalapril. In adult control rats (23 weeks old), the cortical HA content was very low [about 5 microg g(-1) dry weight (d.w.)] and about 1% of the papillary HA content. In rats treated neonatally with enalapril (days 3-13), the cortical HA level was 15 times that in control rats already at 21 days after birth, and it persisted at this level during adulthood (at 23 weeks). At 13 weeks the enalapril-treated animals showed markedly reduced ability (-53%) to concentrate urine during 24-h thirst provocation. At 21 days as well as at 23 weeks the enalapril-treated kidneys displayed morphological changes, such as papillary atrophy, dilation of the tubules and cellular infiltration of the cortical tissue. Histochemical staining confirmed the HA quantification assay and revealed a patchy staining for HA located in the same regions as the infiltrating cells. In conclusion, neonatal treatment with the ACE inhibitor enalapril results in renal morphological and functional abnormalities during adulthood. Cortical HA levels are already seriously elevated at day 21 and coexist with infiltrating cells. Besides the known effects of angiotensin II in development, the accumulation of HA in these kidneys may be involved in the genesis of at least the cortical abnormalities in enalapril-treated animals because of the proinflammatory effects and water-binding properties of HA.     

Cisplatin decreases renal cyclooxygenase-2 expression and activity in rats

Aim: Cisplatin (CP) induced acute renal failure (ARF) has previously been associated with decreased urinary prostaglandin E2 (PGE2) excretion and reduced aquaporin 2 (AQP2) expression in kidney collecting duct. In this study we examined the expression of cyclooxygenase (COX)‐1 and ‐2 as well as AQP2 and the Na‐K‐2Cl cotransporter in kidneys from rats with CP induced ARF. Methods: Rats were treated with either CP or saline and followed for 5 days. Kidneys were dissected into three zones and prepared for immunoblotting, quantitative polymerase chain reaction (QPCR) and immunohistochemistry. Renal content and urinary PGE2 excretion was measured. Results: Cisplatin treatment was associated with polyuria and a significant decreased creatinine clearance. Inner medullary PGE2 content and urinary PGE2 excretion was decreased in CP‐treated rats. QPCR and semiquatitative immunoblotting demonstrated that CP treatment reduced COX‐2, AQP2 and Na‐K‐2Cl cotransporter abundance in the different kidney zones, whereas no change in COX‐1 was observed. Results were confirmed by immunohistochemistry. Conclusion: Cyclooxygenase‐2 expression is decreased in inner medulla and cortex. Consistent with this urinary PGE2 levels were reduced. These data suggest that downregulation of COX‐2 is responsible for impaired de novo generation of vasodilatory prostaglandins which may play an important role for the CP induced renal vasoconstriction and development of nephropathy.