Effects of K+-deficient diets with and without NaCl supplementation on Na+, K+, and H2O transporters' abundance along the nephron

Dietary potassium (K+) restriction and hypokalemia have been reported to change the abundance of most renal Na+ and K+ transporters and aquaporin-2 isoform, but results have not been consistent. The aim of this study was to reexamine Na+, K+ and H2O transporters' pool size regulation in response to removing K+ from a diet containing 0.74% NaCl, as well as from a diet containing 2% NaCl (as found in American diets) to blunt reducing total diet electrolytes. Sprague-Dawley rats ( n = 5–6) were fed for 6 days with one of these diets: 2% KCl, 0.74% NaCl (2K1Na, control chow) compared with 0.03% KCl, 0.74% NaCl (0K1Na); or 2% KCl, 2%NaCl (2K2Na) compared with 0.03% KCl, 2% NaCl (0K2Na, Na+ replete). In both 0K1Na and 0K2Na there were significant decreases in: 1) plasma [K+] (<2.5 mM); 2) urinary K+ excretion (<5% of control); 3) urine osmolality and plasma [aldosterone], as well as 4) an increase in urine volume and medullary hypertrophy. The 0K2Na group had the lowest [aldosterone] (172.0 ± 17.4 pg/ml) and lower blood pressure (93.2 ± 4.9 vs. 112.0 ± 3.1 mmHg in 2K2Na). Transporter pool size regulation was determined by quantitative immunoblotting of renal cortex and medulla homogenates. The only differences measured in both 0K1Na and 0K2Na groups were a 20–30% decrease in cortical β-ENaC, 30–40% increases in kidney-specific Ste20/SPS1-related proline/alanine-rich kinase, and a 40% increase in medullary sodium pump abundance. The following proteins were not significantly changed in both the 0 K groups: Na+/H+ exchanger isoform 3; Na+-K+-Cl− cotransporter; Na+-Cl− cotransporter, oxidative stress response kinase-1; renal outer medullary K+ channel; autosomal recessive hypercholesterolemia; c-Src, aquaporin 2 isoform; or renin. Thus, despite profound hypokalemia and renal K+ conservation, we did not confirm many of the changes that were previously reported. We predict that changes in transporter distribution and activity are likely more important for conserving K+ than changes in total abundance.

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Effect of sodium fluoride on concentrating and diluting ability in the rat

AJP Renal Physiology ◽

10.1152/ajprenal.1977.232.4.f335 ◽

1977 ◽

Vol 232 (4) ◽

pp. F335-F340 ◽

Cited By ~ 1

Author(s):

J. D. Wallin ◽

R. A. Kaplan

Keyword(s):

Cyclic Amp ◽

Urine Volume ◽

Free Water ◽

Urine Osmolality ◽

Inhibitory Effect ◽

Sprague Dawley ◽

Free Water Clearance ◽

Sprague Dawley Rats ◽

Direct Inhibitory Effect ◽

Hereditary Hypothalamic Diabetes Insipidus

Mechanisms for the concentrating defect produced by fluoride were examined in the rat. Free-water clearance at all levels of delivery was normal after 5 days of chronic fluoride administration in the hereditary hypothalamic diabetes insipidus rat. In the Sprague-Dawley rats, during moderate fluoride administration (120 micronmol/kg per day), urine osmolality and cyclic AMP excretion decreased and urine volume increased, but after exogenous vasopressin, volume decreased and osmolality and cyclic AMP increased appropriately. During larger daily doses of fluoride (240 micronmol/kg per day) urinary osmolality and cyclic AMP decreased and volume increased, which was similar to the changes seen during lower fluoride dosages, but these parameters did not change after exogenous vasopressin. These data suggest that ascending limb chloride reabsorption is unaltered by fluoride administration; in the presence of sufficient fluoride, collecting tubular cells apparently do not generate cyclic AMP or increase permeability appropriately in response to vasopressin. The postulated defect is felt to be due to either a decrease in ATP availability or to a direct inhibitory effect of fluoride on the vasopressin-dependent cyclic AMP generating system.

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Abstract 16993: Sex Differences in Renal Transporter Profile Indicate Lower Proximal Reabsorption in Females

Circulation ◽

10.1161/circ.132.suppl_3.16993 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Luciana C Veiras ◽

An Tran ◽

Donna L Ralph ◽

Adriana Castello Costa Girardi ◽

Alicia A McDonough

Keyword(s):

Distal Tubule ◽

Sprague Dawley ◽

Volume Load ◽

Sprague Dawley Rats ◽

Lower Blood ◽

Functional Consequences ◽

Blood Pressures ◽

Renal Transporter ◽

Pressure Natriuresis ◽

Quantitative Immunoblotting

Females have lower blood pressure than males before menopause, blunted hypertensive response to AngII, and a leftward shift in pressure natriuresis. Estrogen decreases renal ACE and AT1R and increases NO and AT2R. At the renal transporter level, distal tubule Na+-Cl- cotransporter (NCC) is upregulated by estrogen and more abundant in females, while the loop of Henle (LH) Na+-K+-2Cl- cotransporter (NKCC2) is less abundant. This study aimed to compare female to male apical Na+ transporters’ abundance, distribution, phosphorylation and cleavage and to determine the functional consequences of the differences. Sprague Dawley rats were fasted overnight then fed a 0%KCl meal before termination. The figure displays relative abundance of total and modified (P -phosphorylated, CL-cleaved, FL-full length) transporters expressed along the nephron in females versus males (defined as 1.0), determined by quantitative immunoblotting. Lower abundance of NaPi2, villin, myosin VI, together with higher NHE3-P (inactivation marker) suggest less proximal tubule (PT) reabsorption in females. Confocal immunohistochemistry confirmed that NHE3 localized to the base of the PT microvilli in females (not males) and endogenous CLi+, a marker of volume leaving the PT, was twice as high in females than males. While LH NKCC2 and its regulatory kinase SPAK were not significantly different, distal NCC, and activated NCC-P were more abundant in females, although thiazide sensitive natriuresis was not greater. ENaC α and γ subunits were more activated (-CL) in females. A saline challenge (7% of b.w. saline, i.p.) demonstrated that females excreted a saline load more rapidly than males. Taken together, these results suggest that lower proximal transporters and reabsorption provoke a volume load dependent elevation in NCC and ENaC. This profile in females likely facilitates pressure natriuresis and maintains lower blood pressures.

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Expression of transporters involved in urine concentration recovers differently after cessation of lithium treatment

AJP Renal Physiology ◽

10.1152/ajprenal.00424.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. F601-F608 ◽

Cited By ~ 24

Author(s):

Mitsi A. Blount ◽

Jae H. Sim ◽

Rong Zhou ◽

Christopher F. Martin ◽

Wei Lu ◽

...

Keyword(s):

Lithium Treatment ◽

Urine Volume ◽

Urine Osmolality ◽

Urine Concentration ◽

Lithium Therapy ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Rapid Restoration ◽

Critical Components ◽

Immunohistochemical Analyses

Patients receiving lithium therapy, an effective treatment for bipolar disorder, often present with acquired nephrogenic diabetes insipidus. The nephrotoxic effects of lithium can be detected 3 wk after the start of treatment and many of these symptoms may disappear in a few weeks after lithium use is stopped. Most patients, however, still have a urine-concentrating defect years after ending treatment. This prompted an investigation of the transporters involved in the urine concentration mechanism, UT-A1, UT-A3, aquaporin-2 (AQP2), and NKCC2, after discontinuing lithium therapy. Sprague-Dawley rats fed a Li2CO3-supplemented diet produced large volumes of dilute urine after 14 days. After lithium treatment was discontinued, urine osmolality returned to normal within 14 days but urine volume and urine urea failed to reach basal levels. Western blot and immunohistochemical analyses revealed that both urea transporters UT-A1 and UT-A3 were reduced at 7 and 14 days of lithium treatment and both transporters recovered to basal levels 14 days after discontinuing lithium administration. Similar analyses demonstrated a decrease in AQP2 expression after 7 and 14 days of lithium therapy. AQP2 expression increased over the 7 and 14 days following the cessation of lithium but failed to recover to normal levels. NKCC2 expression was unaltered during the 14-day lithium regimen but did increase 14 days after the treatment was stopped. In summary, the rapid restoration of UT-A1 and UT-A3 as well as the increased expression of NKCC2 are critical components to the reestablishment of urine concentration after lithium treatment.

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Abstract 114: K+ Rich Diet During Angiotensin II Hypertension Reduces Renal Na-Cl Cotransporter and Phosphorylation, but Not Blood Pressure

Hypertension ◽

10.1161/hyp.66.suppl_1.114 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Luciana C Veiras ◽

Jiyang Han ◽

Donna L Ralph ◽

Alicia A McDonough

Keyword(s):

Blood Pressure ◽

Urine Volume ◽

Weight Ratio ◽

Distal Tubule ◽

Reduce Blood Pressure ◽

Ang Ii ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

K Secretion ◽

Pressure Natriuresis

During Ang II hypertension distal tubule Na-Cl Cotransporter (NCC) abundance and its activating phosphorylation (NCCp), as well as Epithelial Na+ channels (ENaC) abundance and activating cleavage are increased 1.5-3 fold. Fasting plasma [K+] is significantly lower in Ang II hypertension (3.3 ± 0.1 mM) versus controls (4.0 ± 0.1 mM), likely secondary to ENaC stimulation driving K+ secretion. The aim of this study was to test the hypothesis that doubling dietary K+ intake during Ang II infusion will lower NCC and NCCp abundance to increase Na+ delivery to ENaC to drive K+ excretion and reduce blood pressure. Methods: Male Sprague Dawley rats (225-250 g; n= 7-9/group) were treated over 2 weeks: 1) Control 1% K diet fed (C1K); 2) Ang II infused (400 ng/kg/min) 1% K diet fed (A1K); or 3) Ang II infused 2% K diet fed (A2K). Blood pressure (BP) was determined by tail cuff, electrolytes by flame photometry and transporters’ abundance by immunoblot of cortical homogenates. Results: As previously reported, Ang II infusion increased systolic BP (from 132 ± 5 to 197 ± 4 mmHg), urine volume (UV, 2.4 fold), urine Na+ (UNaV, 1.3 fold), heart /body weight ratio (1.23 fold) and clearance of endogenous Li+ (CLi, measures fluid volume leaving the proximal tubule, from 0.26 ± 0.02 to 0.51 ± 0.01 ml/min/kg) all evidence for pressure natriuresis. A2K rats exhibited normal plasma [K+] (4.6 ± 0.1 mM, unfasted), doubled urine K+ (UKV, from 0.20 to 0.44 mmol/hr), and increased CLi (to 0.8 ± 0.1 ml/min/kg) but UV, UNaV, cardiac hypertrophy and BP were unchanged versus the A1K group. As expected, NCC, NCCpS71 and NCCpT53 abundance increased in the A1K group to 1.5 ± 0.1, 2.9 ± 0.5 and 2.8 ± 0.4 fold versus C1K, respectively. As predicted by our hypothesis, when dietary K+ was doubled (A2K), Ang II infusion did not activate NCC, NCCpS71 nor NCCpT53 (0.91 ± 0.04, 1.3 ± 0.1 and 1.6 ± 0.2 fold versus C1K, respectively). ENaC subunit abundance and cleavage increased 1.5 to 3 fold in both A1K and A2K groups; ROMK was unaffected by Ang II or dietary K. In conclusion, evidence is presented that stimulation of NCC during Ang II hypertension is secondary to K+ deficiency driven by ENaC stimulation since doubling dietary K+ prevents the activation. The results also indicate that elevation in BP is independent of NCC activation

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Increased renal α-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape

AJP Renal Physiology ◽

10.1152/ajprenal.00390.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. F49-F57 ◽

Cited By ~ 11

Author(s):

Swasti Tiwari ◽

Randall K. Packer ◽

Xinqun Hu ◽

Yoshihisa Sugimura ◽

Joseph G. Verbalis ◽

...

Keyword(s):

Blood Pressure ◽

Urine Volume ◽

Sprague Dawley ◽

Α Subunit ◽

Water Load ◽

Arterial Blood ◽

Sprague Dawley Rats ◽

Solid Diet ◽

Epithelial Sodium Channel Enac

Previously, we demonstrated that rats undergoing vasopressin escape had increased mean arterial blood pressure (MAP), plasma and urine aldosterone, and increased renal protein abundance of the α-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter (NCC), and the 70-kDa band of γ-ENaC (Song J, Hu X, Khan O, Tian Y, Verbalis JG, and Ecelbarger CA. Am J Physiol Renal Physiol 287: F1076–F1083, 2004; Ecelbarger CA, Knepper MA, and Verbalis JG. J Am Soc Nephrol 12: 207–217, 2001). Here, we determine whether changes in these renal proteins and MAP require elevated aldosterone levels. We performed adrenalectomies (ADX) or sham surgeries on male Sprague-Dawley rats. Corticosterone and aldosterone were replaced to clamp these hormone levels. MAP was monitored by radiotelemetry. Rats were infused with 1-deamino-[8-d-arginine]-vasopressin (dDAVP) via osmotic minipumps (5 ng/h). At day 3 of dDAVP infusion, seven rats in each group were offered a liquid diet [water load (WL)] or continued on a solid diet (SD). Plasma aldosterone and corticosterone and urine aldosterone were increased by WL in sham rats. ADX-WL rats escaped, as assessed by early natriuresis followed by diuresis; however, urine volume and natriuresis were somewhat blunted. WL did not reduce the abundance or activity of 11-β-hydroxsteroid dehydrogenase type 2. Furthermore, the previously observed increase in renal aldosterone-sensitive proteins and escape-associated increased MAP persisted in clamped rats. The densitometry of immunoblots for NCC, α- and γ-70 kDa ENaC, respectively, were (% sham-SD): sham-WL, 159, 278, 233; ADX-SD, 69, 212, 171; ADX-WL, 116, 302, 161. However, clamping corticosteroids blunted the rise at least for NCC and γ-ENaC (70 kDa). Overall, the increase in aldosterone observed in vasopressin escape is not necessary for the increased expression of NCC, α- or γ-ENaC or increased MAP associated with “escape.”

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Differing renal effects of activated and nonactivated isoelectric peaks of human prorenin in rats

AJP Renal Physiology ◽

10.1152/ajprenal.1991.261.6.f975 ◽

1991 ◽

Vol 261 (6) ◽

pp. F975-F981

Author(s):

J. K. McKenzie ◽

D. R. Jones ◽

I. M. McKenzie ◽

D. D. Smyth

Keyword(s):

Physiological Function ◽

Urine Volume ◽

Sprague Dawley ◽

Urine Sodium ◽

Sodium Potassium ◽

Renal Effects ◽

Sprague Dawley Rats ◽

Isoelectric Points ◽

First Time ◽

Ovarian Follicular Fluid

Isoelectric species of renin are physically heterogeneous. Recent evidence suggests that they may differ functionally, with some species producing natriuresis and diuresis, whereas others have no effect. A physiological function of secreted prorenin has not been documented in any species. The present study was designed to confirm and describe for the first time the renal effects of certain isoelectric species of prorenin. Anesthetized Sprague-Dawley rats were injected (0.1 ml) with trypsin-activated or nonactivated prorenin obtained from human ovarian follicular fluid. The dose chosen was calculated as sufficient to produce 2,300 ng angiotensin I.h-1.100 g rat body wt-1 in the presence of excess sheep substrate. Blood pressure, creatinine clearance, urine flow rate, and urine sodium, potassium, and osmolar excretion were measured. Activated prorenin from isoelectric peaks at isoelectric points (pI) 5.1, 5.2, 5.4, and 5.6 produced marked increases in urine volume (sixfold) and sodium excretion (7- to 10-fold) compared with the group receiving the vehicle (1% albumin in 0.9% saline). Activated prorenin from peaks at pI 4.9 and 5.8 produced no significant increase over the vehicle-only experiments. Captopril pretreatment (1 mg/kg iv) completely blocked the effects of peaks at pI 5.4 and 5.6. Interestingly, injection of nonactivated prorenin from peaks at pI 5.4 and 5.6 produced effects similar to the injection of activated prorenin from these peaks. Similarly, this effect was blocked by pretreatment with captopril. In summary, only certain isoelectric peaks of human prorenin whether activated, to active renin, or nonactivated produced a marked natriuresis and diuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

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Vasopressin-dependent upregulation of aquaporin-2 gene expression in glucocorticoid-deficient rats

AJP Renal Physiology ◽

10.1152/ajprenal.2000.279.3.f502 ◽

2000 ◽

Vol 279 (3) ◽

pp. F502-F508 ◽

Cited By ~ 45

Author(s):

Takako Saito ◽

San-E Ishikawa ◽

Fumiko Ando ◽

Minori Higashiyama ◽

Shoichiro Nagasaka ◽

...

Keyword(s):

Gene Expression ◽

Load Test ◽

Sprague Dawley ◽

Water Excretion ◽

Water Load ◽

Aquaporin 2 ◽

Sprague Dawley Rats ◽

Glucocorticoid Deficiency ◽

Aqp2 Gene ◽

Impaired Water

We determined alterations in renal aquaporin-2 (AQP2) gene expression in association with impaired water excretion in glucocorticoid-deficient rats. After adrenalectomy, Sprague-Dawley rats were administered aldosterone alone by osmotic pumps (glucocorticoid-deficient rats). As a control, both aldosterone and dexamethasone were administered. These animals were subjected to the studies on days 7–14. The expressions of AQP2 mRNA and protein in kidney of the glucocorticoid-deficient rats were increased by 1.6- and 1.4-fold compared with the control rats, respectively. An acute oral water load test verified the marked impairment in water excretion in the glucocorticoid-deficient rats. One hour after the water load, the expressions of AQP2 mRNA and protein were significantly reduced in the control rats, but they remained unchanged in the glucocorticoid-deficient rats. However, there was no alteration in [3H]arginine vasopressin (AVP) receptor binding and AVP V2 receptor mRNA expression in the glucocorticoid-deficient rats. A V2-receptor antagonist abolished the increased expressions of AQP2 mRNA and protein in the glucocorticoid-deficient rats. These results indicate that augmented expression of AQP2 participates in impaired water excretion, dependent on AVP, in glucocorticoid deficiency.

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Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin

AJP Cell Physiology ◽

10.1152/ajpcell.00394.2003 ◽

2004 ◽

Vol 286 (5) ◽

pp. C1019-C1030 ◽

Cited By ~ 33

Author(s):

Hassane Amlal ◽

Sulaiman Sheriff ◽

Manoocher Soleimani

Keyword(s):

Metabolic Acidosis ◽

Mrna Expression ◽

Collecting Duct ◽

Urine Volume ◽

Urine Osmolality ◽

Northern Hybridization ◽

Water Control ◽

Expression Levels ◽

Aquaporin 2 ◽

Mrna Expression Levels

Metabolic acidosis is associated with alteration in fluid and electrolyte reabsorption in a number of nephron segments. However, the effects of metabolic acidosis on urine osmolality and aquaporin-2 (AQP-2) remain poorly understood. In these studies, we examined the effects of chronic metabolic acidosis on water handling by the kidney. Rats were placed in metabolic cages and subjected to water (control) or 280 mM NH4Cl loading for 120 h to induce metabolic acidosis. The results indicated a significant increase in urine osmolality with no change in urine volume or urinary Na+ excretion in acid-loaded animals. This effect was independent of alteration in fluid intake or salt/Cl- loading. Immunoblotting and Northern hybridization studies indicated that AQP-2 protein abundance and mRNA expression levels increased significantly along the collecting duct system of NH4Cl-but not NaCl-loaded animals. RIA results indicated that metabolic acidosis was associated with a fourfold increase in circulating levels of vasopressin (AVP) and a significant increase in brain AVP mRNA expression levels. In conclusion, metabolic acidosis upregulates the expression levels of AQP-2 and increases urine osmolality, suggesting an adaptive increase in water reabsorption in the collecting duct. A concomitant increase in AVP synthesis and secretion likely plays an essential role in the adaptation of AQP-2 in metabolic acidosis.

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Increased blood pressure, aldosterone activity, and regional differences in renal ENaC protein during vasopressin escape

AJP Renal Physiology ◽

10.1152/ajprenal.00075.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. F1076-F1083 ◽

Cited By ~ 26

Author(s):

Jian Song ◽

Xinqun Hu ◽

Osman Khan ◽

Ying Tian ◽

Joseph G. Verbalis ◽

...

Keyword(s):

Blood Pressure ◽

Regional Differences ◽

Water Retention ◽

Urine Volume ◽

Hydroxysteroid Dehydrogenase ◽

Plasma Aldosterone ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Sustained Increase

The syndrome of inappropriate antidiuretic hormone (SIADH) is associated with water retention and hyponatremia. The kidney adapts via a transient natriuresis and persistent diuresis, i.e., vasopressin escape. Previously, we showed an increase in the whole kidney abundance of aldosterone-sensitive proteins, the α- and γ (70-kDa-band)-subunits of the epithelial Na+ channel (ENaC), and the thiazide-sensitive Na-Cl cotransporter (NCC) in our rat model of SIADH. Here we examine mean arterial pressure via radiotelemetry, aldosterone activity, and cortical vs. medullary ENaC subunit and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) protein abundances in escape. Eighteen male Sprague-Dawley rats (300 g) were sham operated ( n = 6) or infused with desmopressin (dDAVP; n = 12, a V2 receptor-selective analog of AVP). After 4 days, one-half of the rats receiving dDAVP were switched to a liquid diet, i.e., water loaded (WL) for 5–7 additional days. The WL rats had a sustained increase in urine volume and blood pressure (122 vs. 104 mmHg, P < 0.03, at 7 days). Urine and plasma aldosterone levels were increased in the WL group to 844 and 1,658% of the dDAVP group, respectively. NCC and α- and γ-ENaC (70-kDa band) were increased significantly in the WL group (relative to dDAVP), only in the cortex. β- and γ-ENaC (85-kDa band) were increased significantly by dDAVP in cortex and medulla relative to control. 11β-HSD-2 was increased by dDAVP in the cortex and not significantly affected by water loading. These changes may serve to attenuate Na+ losses and ameliorate hyponatremia in vasopressin escape.

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Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla

AJP Renal Physiology ◽

10.1152/ajprenal.00547.2011 ◽

2012 ◽

Vol 303 (6) ◽

pp. F900-F905 ◽

Cited By ~ 4

Author(s):

Tobias N. von Bergen ◽

Mitsi A. Blount

Keyword(s):

Lupus Erythematosus ◽

Urine Analysis ◽

Water Channel ◽

Chronic Administration ◽

Urine Osmolality ◽

Urine Concentration ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Chloroquine Treatment ◽

Camp Levels

Chloroquine, a widely used anti-malaria drug, has gained popularity for the treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV). Unfortunately, chloroquine may also negatively impact renal function for patients whose fluid and electrolyte homeostasis is already compromised by diseases. Chronic administration of chloroquine also results in polyuria, which may be explained by suppression of the antidiuretic response of vasopressin. Several of the transporters responsible for concentrating urine are vasopressin-sensitive including the urea transporters UT-A1 and UT-A3, the water channel aquaporin-2 (AQP2), and the Na+-K+-2Cl−cotransporter (NKCC2). To examine the effect of chloroquine on these transporters, Sprague-Dawley rats received daily subcutaneous injections of 80 mg·kg−1·day−1of chloroquine for 4 days. Twenty-four hour urine output was twofold higher, and urine osmolality was decreased by twofold in chloroquine-treated rats compared with controls. Urine analysis of treated rats detected the presence chloroquine as well as decreased urine urea and cAMP levels compared with control rats. Western blot analysis showed a downregulation of AQP2 and NKCC2 transporters; however, UT-A1 and UT-A3 abundances were unaffected by chloroquine treatment. Immunohistochemistry showed a marked reduction of UT-A1 and AQP2 in the apical membrane in inner medullary collecting ducts of chloroquine-treated rats. In conclusion, chloroquine-induced polyuria likely occurs as a result of lowered cAMP production. These findings suggest that chronic chloroquine treatment would exacerbate the already compromised fluid homeostasis observed in diseases like chronic kidney disease.

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