Downregulation of renal aquaporins in response to unilateral ureteral obstruction

2003 ◽  
Vol 284 (5) ◽  
pp. F1066-F1079 ◽  
Author(s):  
Chunling Li ◽  
Weidong Wang ◽  
Mark A. Knepper ◽  
Søren Nielsen ◽  
Jørgen Frøkiær
Keyword(s):  
Ureteral Obstruction ◽  
Free Water ◽  
Urine Osmolality ◽  
Wistar Rat ◽  
Unilateral Ureteral Obstruction ◽  
Urinary Concentration ◽  
Outer Medulla ◽  
Bb Rats ◽  
Urine Production ◽  
Aqp1 Expression

The expression of aquaporin-2 (AQP2) is decreased in rats with bilateral ureteral obstruction (BUO) and unilateral ureteral obstruction (UUO). Therefore, the expression of additional renal aquaporins (AQP1–4) and phosphorylated AQP2 (p-AQP2), known to play a role in urinary concentration, was examined in a Wistar rat model with 24 h of UUO. In obstructed kidneys, immunoblotting revealed a significant decrease in the expression of inner medullary AQP2 to 42 ± 4, p-AQP2 to 23 ± 5, AQP3 to 19 ± 6, AQP4 to 11 ± 5, and AQP1 to 64 ± 8% of sham levels. AQP1 expression located in the proximal tubule decreased to 74 ± 4% of sham levels ( P < 0.05). Immunocytochemistry confirmed the downregulation of AQP3, AQP4, and p-AQP2. In contralateral nonobstructed kidneys, immunoblotting also revealed significant reductions of AQP1 in the inner medulla, outer medulla, and cortex, whereas expression of AQP2, AQP3, AQP4, and p-AQP2 was unchanged. Furthermore, we collected the urine from both obstructed and nonobstructed kidneys for 2 h, respectively, after 24 h of UUO. Urine collection from obstructed kidneys during 2 h after release of UUO revealed a significant reduction in urine osmolality and solute-free water reabsorption (TcH2O). Moreover, an increase in urine production and TcH2O was observed in contralateral kidneys. To examine whether vasopressin-independent mechanisms are involved in AQP2 regulation, vasopressin-deficient Brattleboro (BB) rats with 24 h of UUO were examined. Immunoblotting revealed downregulation of AQP2, p-AQP2, AQP3, and AQP1 in obstructed kidneys and downregulation of p-AQP2 and AQP1 in nonobstructed kidneys. In conclusion, 1) UUO is associated with severe downregulation of AQP2, AQP3, AQP4, and AQP1; thus all of these AQPs may play important roles in the impaired urinary concentrating capacity in the obstructed kidney; 2) the reduced levels of AQP1 in the nonobstructed kidney may contribute to the compensatory increase in urine production; and 3) downregulation of AQPs in BB rats supports the view that vasopressin-independent pathways may be involved in AQP2 and AQP3 regulation in the obstructed kidney.

scholarly journals Reduced AQP1, -2, and -3 levels in kidneys of rats with CRF induced by surgical reduction in renal mass

1998 ◽  
Vol 275 (5) ◽  
pp. F724-F741 ◽  
Author(s):  
Tae-Hwan Kwon ◽  
Jørgen Frøkiaer ◽  
Mark A. Knepper ◽  
Søren Nielsen
Keyword(s):  
Urine Output ◽  
Renal Mass ◽  
Collecting Duct ◽  
Free Water ◽  
Urine Osmolality ◽  
Urinary Concentration ◽  
Water Reabsorption ◽  
Similar Reduction ◽  
Urine Production ◽  
Quantitative Immunoblotting

Urinary concentration characteristically decreases in response to a reduction in renal mass in chronic renal failure (CRF). In the present study, we examined whether there are changes in the expression of aquaporins in rats where CRF was induced by 5/6 nephrectomy. Plasma creatinine levels were significantly elevated consistent with significant CRF: 135.7 ± 15.1 ( n = 17, CRF) vs. 33.9 ± 1.1 μmol/l ( n = 11, sham), P < 0.05. Two weeks after 5/6 nephrectomy, the remnant kidneys were hypertrophied, and total renal mass increased to 65 ± 3% of sham levels ( P < 0.05). Urine production increased markedly from 40 ± 2 to 111 ± 3 μl ⋅ min−1 ⋅ kg−1in CRF rats ( P < 0.05), whereas urine osmolality and solute-free water reabsorption decreased significantly. Quantitative immunoblotting of total kidney membrane fractions revealed a significant decrease in total kidney AQP2 expression in CRF rats to 43 ± 12% of sham levels ( P < 0.05). A similar reduction was observed for AQP1 and AQP3. Furthermore, the increased urine output and decreased urine osmolality persisted in CRF rats despite 7 days treatment with 1-desamino-[8-d-arginine]vasopressin (DDAVP, 0.1 μg/h sc) compared with untreated sham-operated controls. Also, there was no change in AQP2 expression (which remained at 38 ± 3% of sham levels, P < 0.05), urine output, or urine osmolality between CRF rats with or without DDAVP treatment. Immunocytochemistry confirmed the decreased AQP2 expression in collecting duct principal cells in CRF rats, with a predominant apical labeling. In conclusion, the results demonstrated that there was a significant vasopressin-resistant downregulation of AQP2 and AQP3 as well as downregulation of AQP1 associated with the polyuria in CRF rats.

AQP3, p-AQP2, and AQP2 expression is reduced in polyuric rats with hypercalcemia: prevention by cAMP-PDE inhibitors

2002 ◽  
Vol 283 (6) ◽  
pp. F1313-F1325 ◽  
Author(s):  
Weidong Wang ◽  
Chunling Li ◽  
Tae-Hwan Kwon ◽  
Mark A. Knepper ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Vitamin D ◽  
Collecting Duct ◽  
Urine Osmolality ◽  
Outer Medulla ◽  
Camp Phosphodiesterase ◽  
Aqp4 Expression ◽  
Pde Inhibitors ◽  
Aqp1 Expression ◽  
Outer Stripe ◽  
Inhibitor Treatment

The purpose of this study was to evaluate whether hypercalcemia is associated with downregulation of renal aquaporins (AQPs), including AQP1, AQP2, phosphorylated AQP2 (p-AQP2), AQP3, and AQP4, and if this is the case, to test whether cAMP-phosphodiesterase (PDE) inhibitor treatment can prevent AQP downregulation and prevent the development of polyuria. Vitamin D-induced hypercalcemia in rats was associated with increased urine output and reduced urine osmolality, consistent with previous findings (Levi M, Peterson L, and Berl T. Kidney Int 23: 489–497, 1983). Semiquantitative immunoblotting revealed a significant reduction in the abundance of inner medullary AQP2 (52 ± 6% of control levels), consistent with previous studies, and of AQP2, which is phosphorylated at the PKA phosphorylation consensus site serine 256 (p-AQP2; 36 ± 8%). Moreover, AQP3 abundance was also significantly decreased (45 ± 7 and 61 ± 6% of control levels in inner medulla and whole kidney, respectively). Consistent with this, immunohistochemistry demonstrated reduced AQP3 immunolabeling along the entire collecting duct. AQP4 expression was not reduced. Surprisingly, total kidney AQP1 abundance was also reduced (60 ± 6%). AQP1 expression was reduced in the cortex and outer stripe of the outer medulla (48 ± 7%; i.e., in proximal tubules). In contrast, AQP1 levels were not changed in the inner stripe of the outer medulla or in the inner medulla (i.e., descending thin limbs and vasa recta). Treatment with the cAMP-PDE inhibitors rolipram and milrinone in combination (inhibiting PDE IV and PDE III isoenzymes) at day 2 and onward completely prevented the hypercalcemia-induced downregulation of AQP2 and AQP3 (but not AQP1) and completely prevented the development of polyuria. In conclusion, AQP3, AQP2, and p-AQP2 are downregulated and are likely to play critical roles in the development of polyuria associated with vitamin D-induced hypercalcemia. Moreover, PDE inhibitor treatment significantly prevented the reduced expression of collecting duct AQPs and prevented the development of polyuria.

scholarly journals Alteration of renal cyclooxygenase expression due to partial unilateral ureteral obstruction in neonatal

2013 ◽  
Vol 7 (3-4) ◽  
pp. E150-155
Author(s):  
Zhi Qin Li ◽  
Yi Zhang ◽  
Qi Li ◽  
Shu Huan Wu ◽  
Chang Yu Sun ◽  
...  
Keyword(s):  
Ureteral Obstruction ◽  
Urine Osmolality ◽  
Plasma Potassium ◽  
Unilateral Ureteral Obstruction ◽  
Sham Operation ◽  
Renal Handling ◽  
Altered Expression ◽  
Water Handling ◽  
Cox 2 ◽  
Cox 1

Introduction: Impaired renal water handling in response to neonatally-induced partial unilateral ureteral obstruction (PUUO) may be associated with altered expression of cyclooxygenase (COX). The purpose of the present study was to examine whether long-term PUUO induced at birth was associated with changes of COX-2.Methods: Rats were subjected to PUUO (n = 14) or a sham operation (n = 12) within the first 48 hours of life. The rats were divided into 4 groups: (1) PUUO at 9 weeks (n = 7); (2) the sham operation at 9 weeks (n = 6); (3) PUUO at 15 weeks (n = 7); and (4) the sham operation at 15 weeks (n = 6). Urine and blood samples were collected before sacrificing the animals. Plasma potassium, creatinine and urea, as well as the osmolality and sodium of plasma and urine were tested in each sample. The expression of renal COX-1 and COX-2 was examined at 9 and 15 weeks in rats with neonatally inducedPUUO within the first 48 hours of life by immunoblotting and immunocytochemistry.Results: PUUO caused a marked decrease in urine osmolality and a significant increase in urinary sodium of the obstructed kidney compared with the sham-operated kidney at 9 and 15 weeks. Immunoblotting analysis showed that an abundance of COX-2 in the obstructed kidney significantly increased compared with the non-obstructed kidney and sham-operated kidney at 9 weeks (p < 0.05) and 15 weeks (p < 0.05) in rats with PUUO. In contrast, COX-1 abundance in the obstructed kidney was similar to that in the non-obstructed kidney. Immunocytochemistry confirmed these findings.Conclusion: Renal COX-2 expression in the obstructed kidney is significantly altered in response to neonatally-induced PUUO. A marked increase in COX-2 indicates that it may be an important factor in reducing renal handling of sodium and water in response to PUUO.

Altered expression of major renal Na transporters in rats with unilateral ureteral obstruction

2003 ◽  
Vol 284 (1) ◽  
pp. F155-F166 ◽  
Author(s):  
Chunling Li ◽  
Weidong Wang ◽  
Tae-Hwan Kwon ◽  
Mark A. Knepper ◽  
Søren Nielsen ◽  
...  
Keyword(s):  
Ureteral Obstruction ◽  
Molecular Mechanisms ◽  
Free Water ◽  
Fractional Excretion ◽  
Unilateral Ureteral Obstruction ◽  
Altered Expression ◽  
Compensatory Increase ◽  
Type 3

It has been demonstrated previously that ureteral obstruction was associated with downregulation of renal AQP2 expression and an impaired urinary concentrating capacity (Li C, Wang W, Kwon TH, Isikay L, Wen JG, Marples D, Djurhuus JC, Stockwell A, Knepper MA, Nielsen S, and Frøkiær J. Am J Physiol Renal Physiol 281: F163–F171, 2001). In the present study, changes in the expression of major renal Na transporters were examined in a rat model with 24 h of unilateral ureteral obstruction (UUO) to clarify the molecular mechanisms of the marked natriuresis seen after release of UUO. Urine collection for 2 h after release of UUO revealed a significant reduction in urinary osmolality, solute-free water reabsorption, and a marked natriuresis (0.29 ± 0.03 vs. 0.17 ± 0.03 μmol/min, P < 0.05). Consistent with this, immunoblotting revealed significant reductions in the abundance of major renal Na transporters: type 3 Na+/H+exchanger (NHE3; 24 ± 4% of sham-operated control levels), type 2 Na-Pi cotransporter (NaPi-2; 21 ± 4%), Na-K-ATPase (37 ± 4%), type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1; 15 ± 3%), and thiazide-sensitive Na-Cl cotransporter (TSC; 15 ± 4%). Immunocytochemistry confirmed the downregulation of NHE3, BSC-1, and TSC in response to obstruction. In nonobstructed contralateral kidneys, a significant reduction in the abundance of inner medullary Na-K-ATPase and cortical NaPi-2 was found. This may contribute to the compensatory increase in urinary production (23 ± 2 vs. 13 ± 1 μl · min−1 · kg−1) and increased fractional excretion of urinary Na (0.62 ± 0.03 vs. 0.44 ± 0.03%, P < 0.05). In conclusion, downregulation of major renal Na transporters in rats with UUO may contribute to the impairment in urinary concentrating capacity and natriuresis after release of obstruction, and reduced levels of Na-K-ATPase and NaPi-2 in the contralateral nonobstructed kidney may contribute to the compensatory increase in water and Na excretion from that kidney during UUO and after release of obstruction.

Effects of subpicomolar changes in vasopressin on urinary concentration

1988 ◽  
Vol 255 (6) ◽  
pp. R940-R945 ◽  
Author(s):  
M. Baerwolff ◽  
P. Bie
Keyword(s):  
Free Water ◽  
Urine Osmolality ◽  
Urinary Concentration ◽  
Metabolic Clearance ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Control Series ◽  
Water Load ◽  
Small Increments ◽  
Solute Excretion

The possibility that small amounts of vasopressin (AVP) reduce water excretion without affecting solute excretion was investigated in conscious dogs. AVP was infused intravenously for 120 min at rates of 2 and 5 pg.min-1.kg body wt-1 during water diuresis elicited by a sustained water load of 2% body wt. During control experiments urine osmolality was constantly approximately 60 mosmol/kgH2O; during AVP infusions it increased by factors of 1.36 (P less than 0.01) and 2.12 (P less than 0.01), respectively, concomitant with 39 +/- 6 and 61 +/- 7% reductions in urine flow. Osmolar and free water clearances decreased significantly. Sodium excretion did not change; changes in potassium excretion during AVP were similar to those of the control series, i.e., a gradual decline. During AVP, 5 pg.min-1. kg-1, creatinine and urea clearances decreased (25 +/- 2 and 31 +/- 7%, respectively, both P less than 0.01). With the assumption of metabolic clearance rates of AVP of 15-40 ml.min-1.kg body wt-1, the increase in plasma AVP during the infusion of 2 pg.min-1.kg body wt-1 was 5-13 X 10(-14) M. It is concluded that small increments in plasma AVP may reduce glomerular filtration rate and that with increasing levels of AVP in plasma 1) reduction of free water clearance, 2) reduction in urea clearance, and 3) natriuresis-kaliuresis occur in that order. Apparently AVP cannot reduce water excretion without changing the rate of excretion of solutes.

scholarly journals Diminished Renal Expression of Aquaporin Water Channels in Rats with Experimental Bilateral Ureteral Obstruction

2001 ◽  
Vol 12 (10) ◽  
pp. 2019-2028 ◽  
Author(s):  
SOO WAN KIM ◽  
SAM HYEON CHO ◽  
BONG SUK OH ◽  
CHUNG HO YEUM ◽  
KI CHUL CHOI ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Arginine Vasopressin ◽  
Ureteral Obstruction ◽  
Free Water ◽  
Water Channels ◽  
Urinary Flow ◽  
Sprague Dawley ◽  
Outer Medulla ◽  
Camp Generation ◽  
Renal Expression

Abstract. Whether postobstructive diuresis could be related to altered regulation of aquaporin (AQP) water channels in the kidney was investigated. Male Sprague-Dawley rats underwent bilateral obstruction of the proximal ureters for 48 h. The renal expression of AQP1 to AQP4 proteins was then determined by Western blot and immunohistochemical analyses. For elucidation of the primary impairment in the upstream pathway leading to the expression of cAMP-mediated AQP channels, the expression of Gsαand that of adenylyl cyclase were also determined. For some rats, the obstruction was released for collection of urine samples. After the ureteral obstruction, the urinary flow rate was increased and free water reabsorption was decreased. In the obstructed kidneys, the expression of AQP1 to AQP3 was decreased in the cortex, outer medulla, and inner medulla, whereas that of AQP4 was decreased in the inner medulla. Immunoreactivities for AQP1 to AQP4 were also decreased in the obstructed kidneys. The protein expression of Gsαwas decreased in the cortex, outer medulla, and inner medulla, whereas that of adenylyl cyclase VI was decreased in the outer and inner medullae. cAMP generation stimulated by arginine vasopressin was decreased in the cortex, outer medulla, and inner medulla. cAMP generation in response to forskolin was decreased in the outer and inner medullae, whereas that in response to sodium fluoride was decreased in the cortex, outer medulla, and inner medulla. These results suggest that a reduced abundance of AQP water channels in the kidney accounts in part for postobstructive diuresis. The primary impairment of AQP channels that are regulated via the arginine vasopressin/cAMP pathway may lie at the level of G proteins and adenylyl cyclase itself.

Aldosterone increases urine production and decreases apical AQP2 expression in rats with diabetes insipidus

2006 ◽  
Vol 290 (2) ◽  
pp. F438-F449 ◽  
Author(s):  
Jakob Nielsen ◽  
Tae-Hwan Kwon ◽  
Jeppe Praetorius ◽  
Jørgen Frøkiær ◽  
Mark A. Knepper ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Diabetes Insipidus ◽  
Free Water ◽  
Sodium Balance ◽  
Apical Plasma Membrane ◽  
Sodium Reabsorption ◽  
Outer Medulla ◽  
Free Water Clearance ◽  
Urine Production ◽  
Water Clearance

Vasopressin and aldosterone are essential hormones in the regulation of water and sodium balance. Aldosterone regulates sodium reabsorption, although synergistic effects on collecting duct water permeability have been shown. We investigated the effects of 7-day aldosterone infusion or oral spironolactone treatment on water balance and aquaporin (AQP) 2 expression in rats with 21 days of lithium-induced nephrogenic diabetes insipidus (Li-NDI). In rats with Li-NDI, aldosterone markedly increased (271 ± 14 ml/24 h), whereas spironolactone decreased (74 ± 11 ml/24 h) urine production compared with rats treated with lithium only (120 ± 11 ml/24 h). Aldosterone increased free-water clearance and creatinine clearance, whereas spironolactone caused a decreased creatinine clearance but unchanged free-water clearance. Immunoblotting showed unchanged AQP2 expression in cortex/outer stripe of the outer medulla and inner medulla. In the inner stripe of the outer medulla aldosterone caused a decreased AQP2 expression, whereas spironolactone caused an increase compared with rats treated with lithium only. Semiquantitative confocal immunofluorescence microscopy of AQP2 immunolabeling showed reduced AQP2 expression in the apical plasma membrane domain in connecting tubule (CNT) and initial cortical collecting ducts (iCCD) in response to aldosterone-treated rats compared with rats treated with lithium only. Spironolactone significantly increased apical AQP2 expression in the iCCD compared with rats treated with lithium only. We also tested whether similar changes could be observed in vasopressin-deficient BB rats and found similar changes in urine production and subcellular AQP2 expression in the CNT and iCCD in response to aldosterone and spironolactone. This study shows that aldosterone treatment perturbs diabetes insipidus and is associated with AQP2 redistribution in CNT and iCCD likely mediated by the spironolactone-sensitive mineralocorticoid receptor.

Renal activity of vasopressin in anesthetized dogs

1961 ◽  
Vol 200 (2) ◽  
pp. 400-404 ◽  
Author(s):  
Joseph H. Perlmutt
Keyword(s):  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Free Water ◽  
Urine Osmolality ◽  
Urine Flow ◽  
Urinary Concentration ◽  
Urinary Ph ◽  
Free Water Clearance ◽  
Anesthetized Dogs ◽  
Sustained Increase

Conventional clearance techniques were used to study the renal response to vasopressin (5–100 mu/hr.) infused for 2 1/2 hours into anesthetized (pentobarbital), surgically traumatized dogs elaborating a dilute urine. Decreased urine flow, a concomitant sustained increase in Na+ excretion, increased urine osmolality, negative free-water clearance and an increased osmolal U/P ratio (>1, <2) consistently occurred during the infusion of 50 mu/hr. Urinary pH rose and HCO3–, rather than Cl–, was the predominant anion excreted. Tubular rejection of HCO3–, however, is not essential for vasopressin activity under the conditions of this investigation since antidiuresis occurred in an acidotic dog. Usually some increase in glomerular filtration rate and effective renal plasma flow were apparent during vasopressin infusion; the former change could account for the increased Na+ excretion, but it is difficult to ascribe the peculiar anion behavior to this factor. Maximum urinary concentration was not attained even with 100 mu vasopressin/hr.

Urinary Concentration and Dilution after Unilateral Nephrectomy in the Rat

1975 ◽  
Vol 49 (6) ◽  
pp. 563-572
Author(s):  
D. S. Emmanouel ◽  
M. D. Lindheimer ◽  
A. I. Katz
Keyword(s):  
Antidiuretic Hormone ◽  
Free Water ◽  
Urine Osmolality ◽  
Renal Tissue ◽  
Unilateral Nephrectomy ◽  
Urinary Concentration ◽  
Sprague Dawley ◽  
Fluid Delivery ◽  
Sprague Dawley Rats ◽  
Water Formation

1. The effects of unilateral nephrectomy on urinary concentration and dilution were studied in Sprague—Dawley rats. To exclude incomplete suppression of antidiuretic hormone, free water formation was also studied in rats with congenital diabetes insipidus (Brattleboro strain). 2. Urinary solute-free water formation was similar in Sprague—Dawley and Brattleboro rats. Unineph-rectomized animals excreted a water load promptly and diluted their urine to the same degree as control rats. Maximal values for Cwater and TCwater per kidney were higher after nephrectomy, but were similar to those of control rats at comparable rates of fluid delivery to the distal nephron. Renal tissue osmolality was similar in uninephrectomized and sham-operated animals, indicating that non-antidiuretic hormone-dependent backflux of filtrate was the same in the two groups. The only defect observed in uninephrectomized animals was a small reduction in maximal urine osmolality. 3. These results demonstrate that free water formation and reabsorption are unaffected by unilateral nephrectomy and suggest that, in the remaining kidney, filtrate reabsorption along the entire nephron increases in proportion to the increment in glomerular filtration.

scholarly journals Cisplatin Decreases the Abundance of Aquaporin Water Channels in Rat Kidney

2001 ◽  
Vol 12 (5) ◽  
pp. 875-882
Author(s):  
SOO-WAN KIM ◽  
JONG-UN LEE ◽  
MYONG-YUN NAH ◽  
DAE-GILL KANG ◽  
KYU-YOUN AHN ◽  
...  
Keyword(s):  
Arginine Vasopressin ◽  
Rat Kidney ◽  
Free Water ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Water Channels ◽  
Control Group ◽  
Urinary Concentration ◽  
Sprague Dawley ◽  
Outer Medulla

Abstract. The present study examined whether the cisplatininduced urinary concentration defect can be related to an altered regulation of aquaporin (AQP) water channels in the kidney. Cisplatin (8 mg/kg) was injected intraperitoneally into male Sprague-Dawley rats. The control group was without cisplatin treatment. Four d later, the expression of AQP1, AQP2, and AQP3 proteins was determined in the kidney. To specify further the primary point of derangement in the pathway that activates the arginine vasopressin—mediated AQP channels, different components of adenylyl cyclase complex were examined separately. The cisplatin treatment caused a polyuric renal failure in association with decreases of free water reabsorption. The expression of AQP1 and AQP2 was decreased in the cortex, the outer medulla, and the inner medulla, whereas that of AQP3 was decreased in the outer medulla and the inner medulla. The expression of AQP2 proteins in the apical membrane-enriched fraction decreased in parallel with that in the subapical vesicle-enriched fraction, indicating a preserved targeting. Immunohistochemistry of the outer medulla also revealed that cisplatin decreased immunoreactivity for AQP1, AQP2, and AQP3. The arginine vasopressin—evoked generation of cyclic adenosine monophosphate was attenuated by cisplatin, being most prominent in the outer medulla. However, the cyclic adenosine monophosphate generation in response to forskolin was not affected, whereas that to sodium fluoride was diminished significantly. Cisplatin also decreased the expression of Gsα proteins in the outer medulla and the inner medulla. These results suggest that a reduced expression of AQP water channels accounts at least in part for the cisplatin-induced urinary concentration defect.

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