Nephron-specific deletion of the prorenin receptor causes a urine concentration defect

The prorenin receptor (PRR), a recently discovered component of the renin-angiotensin system, is expressed in the nephron in general and the collecting duct in particular. However, the physiological significance of nephron PRR remains unclear, partly due to developmental abnormalities associated with global or renal-specific PRR gene knockout (KO). Therefore, we developed mice with inducible nephron-wide PRR deletion using Pax8-reverse tetracycline transactivator and LC-1 transgenes and loxP flanked PRR alleles such that ablation of PRR occurs in adulthood, after induction with doxycycline. Nephron-specific PRR KO mice have normal survival to ∼1 yr of age and no renal histological defects. Compared with control mice, PRR KO mice had 65% lower medullary PRR mRNA and protein levels and markedly diminished renal PRR immunofluorescence. During both normal water intake and mild water restriction, PRR KO mice had significantly lower urine osmolality, higher water intake, and higher urine volume compared with control mice. No differences were seen in urine vasopressin excretion, urine Na+ and K+ excretion, plasma Na+, or plasma osmolality between the two groups. However, PRR KO mice had reduced medullary aquaporin-2 levels and arginine vasopressin-stimulated cAMP accumulation in the isolated renal medulla compared with control mice. Taken together, these results suggest nephron PRR can potentially modulate renal water excretion.

Download Full-text

Collecting duct principal, but not intercalated, cell prorenin receptor regulates renal sodium and water excretion

AJP Renal Physiology ◽

10.1152/ajprenal.00122.2018 ◽

2018 ◽

Vol 315 (3) ◽

pp. F607-F617 ◽

Cited By ~ 12

Author(s):

Nirupama Ramkumar ◽

Deborah Stuart ◽

Elena Mironova ◽

Nikita Abraham ◽

Yang Gao ◽

...

Keyword(s):

Water Transport ◽

Collecting Duct ◽

Urine Volume ◽

Urine Osmolality ◽

Open Probability ◽

Water Excretion ◽

Intercalated Cell ◽

Water Handling ◽

Prorenin Receptor ◽

Collecting Ducts

The collecting duct is the predominant nephron site of prorenin and prorenin receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na+ channel (ENaC) activity and water transport; however, which cell type is involved remains unclear. Herein, we examined the effects of principal cell (PC) or intercalated cell (IC) PRR deletion on renal Na+ and water handling. PC or IC PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring Cre recombinase under the control of the AQP2 or B1 subunit of the H+ ATPase promoters, respectively. PC KO mice had reduced renal medullary ENaC-α abundance and increased urinary Na+ losses on a low-Na+ diet compared with controls. Conversely, IC KO mice had no apparent differences in Na+ balance or ENaC abundance compared with controls. Acute treatment with prorenin increased ENaC channel number and open probability in acutely isolated cortical collecting ducts from control and IC PRR KO, but not PC PRR KO, mice. Furthermore, compared with controls, PC KO, but not IC KO mice, had increased urine volume, reduced urine osmolality, and reduced abundance of renal medullary AQP2. Taken together, these findings indicate that PC, but not IC, PRR modulates ENaC activity, urinary Na+ excretion, and water transport.

Download Full-text

Collecting duct-specific knockout of adenylyl cyclase type VI causes a urinary concentration defect in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00397.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. F78-F84 ◽

Cited By ~ 42

Author(s):

Karl P. Roos ◽

Kevin A. Strait ◽

Kalani L. Raphael ◽

Mitsi A. Blount ◽

Donald E. Kohan

Keyword(s):

Adenylyl Cyclase ◽

Water Intake ◽

Arginine Vasopressin ◽

Water Deprivation ◽

Collecting Duct ◽

Urine Volume ◽

Urine Osmolality ◽

Camp Accumulation ◽

Water Excretion ◽

Normal Water

Collecting duct (CD) adenylyl cyclase VI (AC6) has been implicated in arginine vasopressin (AVP)-stimulated renal water reabsorption. To evaluate the role of CD-derived AC6 in regulating water homeostasis, mice were generated with CD-specific knockout (KO) of AC6 using the Cre/loxP system. CD AC6 KO and controls were studied under normal water intake, chronically water loaded, or water deprived; all of these conditions were repeated in the presence of continuous administration of 1-desamino-8-d-arginine vasopressin (DDAVP). During normal water intake or after water deprivation, urine osmolality (Uosm) was reduced in CD AC6 KO animals vs. controls. Similarly, Uosm was decreased in CD AC6 KO mice vs. controls after water deprivation+DDAVP administration. Pair-fed (with controls) CD AC6 KO mice also had lower urine osmolality vs. controls. There were no detectable differences between KO and control animals in fluid intake or urine volume under any conditions. CD AC6 KO mice did not have altered plasma AVP levels vs. controls. AVP-stimulated cAMP accumulation was reduced in acutely isolated inner medullary CD (IMCD) from CD A6 KO vs. controls. Medullary aquaporin-2 (AQP2) protein expression was lower in CD AC6 KO mice vs. controls. There were no differences in urinary urea excretion or IMCD UT-A1 expression; however, IMCD UT-A3 expression was reduced in CD AC6 KO mice vs. controls. In summary, AC6 in the CD regulates renal water excretion, most likely through control of AVP-stimulated cAMP accumulation and AQP2.

Download Full-text

Downregulation of renal vasopressin V2 receptor and aquaporin-2 expression parallels age-associated defects in urine concentration

AJP Renal Physiology ◽

10.1152/ajprenal.00403.2003 ◽

2004 ◽

Vol 287 (4) ◽

pp. F797-F805 ◽

Cited By ~ 37

Author(s):

Ying Tian ◽

Ryota Serino ◽

Joseph G. Verbalis

Keyword(s):

Collecting Duct ◽

Water Channel ◽

Age Groups ◽

Urine Osmolality ◽

Brown Norway ◽

Water Restriction ◽

Water Excretion ◽

F1 Hybrid ◽

Young Rats ◽

Aquaporin 2

Renal concentrating ability is known to be impaired with aging. The antidiuretic hormone AVP plays an important role in renal water excretion by regulating the membrane insertion and abundance of the water channel aquaporin-2 (AQP2); this effect is primarily mediated via the V2 subtype of the AVP receptor (V2R). This study evaluated the hypothesis that decreased renal sensitivity to AVP, with subsequent altered renal AQP2 expression, contributes to the reduced urinary concentrating ability with aging. Our results show that under baseline conditions, urine osmolality is significantly lower in aged Fischer 344 and Brown-Norway F1 hybrid (F344BN) rats despite equivalent plasma AVP concentrations as in young rats. Levels of kidney V2R mRNA expression and AQP2 abundances were also significantly decreased in aged F344BN rats, as was AQP2 immunostaining in collecting duct cells. In response to moderate water restriction, urine osmolality increased by significantly lesser amounts in aged F344BN rats compared with young rats despite similar increases in plasma AVP levels. Moderate water restriction induced equivalent relative increases in renal AQP2 abundances in all age groups but resulted in significantly lower abundances in total kidney AQP2 protein in aged compared with young F344BN rats. These results therefore demonstrate a functional impairment of renal concentrating ability in aged F344BN rats that is not due to impaired secretion of AVP but rather appears to be related to impaired responsiveness of the kidney to AVP that is secondary, at least in part, to a downregulation of renal V2R expression and AQP2 abundance.

Download Full-text

The Vasopressin System in the Risk of Diabetes and Cardiorenal Disease, and Hydration as a Potential Lifestyle Intervention

Annals of Nutrition and Metabolism ◽

10.1159/000488304 ◽

2018 ◽

Vol 72 (Suppl. 2) ◽

pp. 21-27 ◽

Cited By ~ 5

Author(s):

Sofia Enhörning ◽

Olle Melander

Keyword(s):

Type 2 Diabetes ◽

Water Intake ◽

Kidney Diseases ◽

Urine Volume ◽

Plasma Osmolality ◽

Premature Mortality ◽

Urine Osmolality ◽

High Plasma ◽

Effective Prevention

Background: Type 2 diabetes, chronic kidney disease (CKD) and its cardiovascular complications are increasing as health problems worldwide. These diseases are interrelated with overlapping occurrence and once diabetes is established, the risk of cardiorenal disease is dramatically elevated. Thus, a search for unifying modifiable risk factors is key for effective prevention. Summary: Elevated fasting plasma concentration of vasopressin, measured with the marker copeptin, predicts new onset type 2 diabetes as well as renal function decline. Furthermore, we recently showed that increased plasma copeptin concentration independently predicts the development of both CKD and other specified kidney diseases. In consequence, high copeptin is an independent risk factor for cardiovascular disease and premature mortality in both diabetes patients and in the general population. Vasopressin is released when plasma osmolality is high, and the easiest way to lower plasma vasopressin and copeptin concentration is to increase water intake. In a human water intervention experiment with 1 week of 3 L/day increased water intake, the one third of the participants with the greatest copeptin reduction (water responders) were those with a phenotype of low water intake (high habitual plasma copeptin and urine osmolality, and low urine volume). The water-responders had a copeptin reduction of 41% after 1 week of increased water intake compared to a control week; in contrast, a 3% reduction occurred in the other two thirds of the study participants. Among water responders, increased water intake also induced a reduction in fasting glucagon concentration. Key Messages: Elevated copeptin, a measure of vasopressin, is a risk marker of metabolic and cardiorenal diseases and may assist in the detection of individuals at higher risk for these diseases. Furthermore, individuals with high copeptin and other signs of low water intake may experience beneficial glucometabolic effects of increased water intake. Future randomized control trials investigating effects of hydration on glucometabolic and renal outcomes should focus on individuals with signs of low water intake including high plasma copeptin concentration.

Download Full-text

Lack of an effect of collecting duct-specific deletion of adenylyl cyclase 3 on renal Na+ and water excretion or arterial pressure

AJP Renal Physiology ◽

10.1152/ajprenal.00505.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. F597-F607 ◽

Cited By ~ 14

Author(s):

Wararat Kittikulsuth ◽

Deborah Stuart ◽

Alfred N. Van Hoek ◽

James D. Stockand ◽

Vladislav Bugaj ◽

...

Keyword(s):

Arterial Pressure ◽

Adenylyl Cyclase ◽

Collecting Duct ◽

Urine Volume ◽

Physiological Role ◽

Plasma Renin ◽

Water Restriction ◽

Water Excretion ◽

And Control

cAMP is a key mediator of connecting tubule and collecting duct (CD) Na+ and water reabsorption. Studies performed in vitro have suggested that CD adenylyl cyclase (AC)3 partly mediates the actions of vasopressin; however, the physiological role of CD AC3 has not been determined. To assess this, mice were developed with CD-specific disruption of AC3 [CD AC3 knockout (KO)]. Inner medullary CDs from these mice exhibited 100% target gene recombination and had reduced ANG II- but not vasopressin-induced cAMP accumulation. However, there were no differences in urine volume, urinary urea excretion, or urine osmolality between KO and control mice during normal water intake or varying degrees of water restriction in the presence or absence of chronic vasopressin administration. There were no differences between CD AC3 KO and control mice in arterial pressure or urinary Na+ or K+ excretion during a normal or high-salt diet, whereas plasma renin and vasopressin concentrations were similar between the two genotypes. Patch-clamp analysis of split-open cortical CDs revealed no difference in epithelial Na+ channel activity in the presence or absence of vasopressin. Compensatory changes in AC6 were not responsible for the lack of a renal phenotype in CD AC3 KO mice since combined CD AC3/AC6 KO mice had similar arterial pressure and renal Na+ and water handling compared with CD AC6 KO mice. In summary, these data do not support a significant role for CD AC3 in the regulation of renal Na+ and water excretion in general or vasopressin regulation of CD function in particular.

Download Full-text

Collecting duct-specific knockout of nitric oxide synthase 3 impairs water excretion in a sex-dependent manner

AJP Renal Physiology ◽

10.1152/ajprenal.00494.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. F1074-F1083 ◽

Cited By ~ 8

Author(s):

Yang Gao ◽

Deborah Stuart ◽

Jennifer S. Pollock ◽

Takamune Takahishi ◽

Donald E. Kohan

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Collecting Duct ◽

Urine Volume ◽

Plasma Renin ◽

Urine Osmolality ◽

Dependent Manner ◽

Water Reabsorption ◽

Water Excretion ◽

Water Loading

Nitric oxide (NO) inhibits collecting duct (CD) Na+ and water reabsorption. Mice with CD-specific knockout (KO) of NO synthase 1 (NOS1) have salt-sensitive hypertension. In contrast, the role of NOS3 in CD salt and water reabsorption is unknown. Mice with CD NOS3 KO were generated with loxP-flanked exons 9–12 (encodes the calmodulin binding site) of the NOS3 gene and the aquaporin-2 promoter-Cre transgene. There were no differences between control and CD NOS3 KO mice, irrespective of sex, in food intake, water intake, urine volume, urinary Na+ or K+ excretion, plasma renin concentration, blood pressure, or pulse during 7 days of normal (0.3%), high (3.17%), or low (0.03%) Na+ intake. Blood pressure was similar between genotypes during DOCA-high salt. CD NOS3 KO did not alter urine volume or urine osmolality after water deprivation. In contrast, CD NOS3 KO male, but not female, mice had lower urine volume and higher urine osmolality over the course of 7 days of water loading compared with control mice. Male, but not female, CD NOS3 KO mice had reduced urinary nitrite+nitrate excretion compared with controls after 7 days of water loading. Urine AVP and AVP-stimulated cAMP accumulation in isolated inner medullary CD were similar between genotypes. Western analysis did not reveal a significant effect of CD NOS3 KO on renal aquaporin expression. In summary, these data suggest that CD NOS3 may be involved in the diuretic response to a water load in a sex-specific manner; the mechanism of this effect remains to be determined.

Download Full-text

Abstract MP34: Collecting Duct Cells-derived Human Sprr Impairs The Antihypertensive Effects Of Losartan And Upregulates Erk1/2 And Aqp2 Expression

Hypertension ◽

10.1161/hyp.78.suppl_1.mp34 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Gertrude Arthur ◽

Audrey Poupeau ◽

Kellea Nichols ◽

Jacqueline Leachman ◽

Analia S Loria ◽

...

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Water Balance ◽

Collecting Duct ◽

Urine Volume ◽

Plasma Osmolality ◽

Standard Diet ◽

Male Mice ◽

Humanized Mouse Model ◽

Prorenin Receptor

Recent studies showed that soluble prorenin receptor (sPRR) plays an important role in blood pressure regulation and in water balance. In rodent models, sPRR contributes to AngII production by increasing renin activity, systolic blood pressure (SBP) and aquaporin2 (AQP2)-dependent antidiuretic action. However, there is a gap of knowledge concerning the functional role of locally produced sPRR from the kidney. Therefore, we evaluated the kidney-derived human sPRR role in SBP control and fluid homeostasis. Human sPRR-Myc-tag transgenic mice were bred with mice expressing Hoxb7/Cre to selectively express human sPRR in the collecting duct (RHsPRR). RHsPRR and control (CTL) male mice were fed a standard diet for 10 months (n=8-11/group). Body weight and urine volume were examined and SBP measured by radiotelemetry. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male mice validating the humanized mouse model. Body weight did not change and 24hr-SBP was similar between CLT and RHsPRR mice (128±2 and 122±5 mmHg, respectively). However, the chronic response to losartan treatment was reduced in RHsPRR compared to CTL (ΔSBP: CTL: -9±3; RHsPRR: -5±1 mmHg, P<0.05). Kidney-derived human sPRR did not change GFR (838±75 vs 1088±163 μl/min/100g BW) and urinary vasopressin (0.62±0.21; 0.72±0.20 ng/mg creatinine), while modestly decreasing urine excretion rate by ~40% (CTL: 1.04±0.20; RHsPRR: 0.57±0.25 ml/day). Furthermore, RHsPRR mice had higher AQP2 protein expression in renal cortex (CTL: 0.24±0.07; RHsPRR: 4.11±0.70 AU, P<0.05) and medulla (CTL: 0.11±0.04; RHsPRR: 4.03±1.74 AU, P<0.05) than CTL mice. Kidney-derived human sPRR significantly increased phosphorylation of ERK 1/2 in the cortex compared to CTL (CTL: 5.4±1.0; RHsPRR: 9.2±1.4 AU, P<0.05), an MAPK involved in the regulation of water balance. In addition, RHsPRR mice showed increased plasma osmolality compared to CTL mice (CTL: 349±2; RHsPRR: 357±2 mOsm/kg, P<0.05). Overall, our data suggest that renal human sPRR could contribute to the increase in plasma tonicity by promoting the activation of ERK1/2-AQP2 pathway. Whether this signaling is associated with impaired antihypertensive effects of AT1R blockage remains under investigation.

Download Full-text

Urine and Plasma Osmolality in Patients with Autosomal Dominant Polycystic Kidney Disease: Reliable Indicators of Vasopressin Activity and Disease Prognosis?

American Journal of Nephrology ◽

10.1159/000382081 ◽

2015 ◽

Vol 41 (3) ◽

pp. 248-256 ◽

Cited By ~ 6

Author(s):

Niek F. Casteleijn ◽

Debbie Zittema ◽

Stephan J.L. Bakker ◽

Wendy E. Boertien ◽

Carlo A. Gaillard ◽

...

Keyword(s):

Water Intake ◽

Plasma Osmolality ◽

Urine Osmolality ◽

Kidney Volume ◽

Polycystic Kidney ◽

Estimated Gfr ◽

Total Kidney Volume ◽

Autosomal Dominant Polycystic Kidney ◽

Crude Analysis

Background: Vasopressin plays an essential role in osmoregulation, but has deleterious effects in patients with ADPKD. Increased water intake to suppress vasopressin activity has been suggested as a potential renoprotective strategy. This study investigated whether urine and plasma osmolality can be used as reflection of vasopressin activity in ADPKD patients. Methods: We measured urine and plasma osmolality, plasma copeptin concentration, total kidney volume (TKV, by MRI) and GFR (125I-iothalamate). In addition, change in estimated GFR (eGFR) during follow-up was assessed. Results: Ninety-four patients with ADPKD were included (56 males, age 40 ± 10, mGFR 77 ± 32 ml/min/1.73 m2, TKV 1.55 (0.99-2.40) l. Urine osmolality, plasma osmolality and copeptin concentration were 420 ± 195, 289 ± 7 mOsmol/l and 7.3 (3.2-14.6) pmol/l, respectively. Plasma osmolality was associated with copeptin concentration (R = 0.54, p < 0.001), whereas urine osmolality was not (p = 0.4). In addition, urine osmolality was not associated with TKV (p = 0.3), in contrast to plasma osmolality (R = 0.52, p < 0.001) and copeptin concentration (R = 0.61, p < 0.001). Fifty-five patients were followed for 2.8 ± 0.8 years. Baseline plasma and urine osmolality were not associated with change in eGFR (p = 0.6 and p = 0.3, respectively), whereas baseline copeptin concentration did show an association with change in eGFR, in a crude analysis (St. β = -0.41, p = 0.003) and also after adjustment for age, sex and TKV (St. β = -0.23, p = 0.05). Conclusions: These data suggest that neither urine nor plasma osmolality are valid measures to identify ADPKD patients that may benefit from increasing water intake. Copeptin appears a better alternative for this purpose.

Download Full-text

(PRO)RENIN RECEPTOR IN THE KIDNEY: FUNCTION AND SIGNIFICANCE

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00259.2020 ◽

2021 ◽

Author(s):

Gertrude Arthur ◽

Jeffrey L. Osborn ◽

Frederique B. Yiannikouris

Keyword(s):

Intracellular Signaling ◽

Collecting Duct ◽

Renin Angiotensin System ◽

Cortical Collecting Duct ◽

Acid Base Balance ◽

Acid Base ◽

Kidney Fibrosis ◽

Prorenin Receptor ◽

Base Balance ◽

And Function

Prorenin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin has been shown to be multifunctional. In addition to its role in the renin angiotensin system (RAS), PRR also transduces several intracellular signaling molecules and is a component of the vacuolar H+-ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney namely the macula densa, podocyte, proximal and distal convoluted tubule and the principal cells of the collecting duct and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.

Download Full-text

Influence of steady-state PaCO2 on escape from ADH-induced water retention in the dog

AJP Renal Physiology ◽

10.1152/ajprenal.1978.234.4.f291 ◽

1978 ◽

Vol 234 (4) ◽

pp. F291-F296

Author(s):

W. D. Kaehny ◽

A. Gougoux ◽

J. J. Cohen

Keyword(s):

Steady State ◽

Water Intake ◽

Water Deprivation ◽

Water Retention ◽

Plasma Osmolality ◽

Similar Extent ◽

Water Excretion ◽

Average Value ◽

Marked Disparity ◽

Per Se

The influence of the prevailing PaCO2 on the water-retaining effects of sustained elevations in ADH was assessed by administering vasopressin (5 U in oil, twice daily) and a fixed water intake to dogs with eucapnia (n, 7), chronic hypercapnia (n, 6), and chronic hypocapnia (n, 8). Although water excretion initially fell to a similar extent in all three groups, cumulative water retention by day 4 of vasopressin administration was 77 mg/kg in the hypocapnic group, 46 ml/kg in the eucapnic group, and only 14 ml/kg in the hypercapnic group. These differences were reflected in a marked disparity in the degree of hyposmolality of body fluids, plasma osmolality falling by day 4 to an average value of 223, 237, and 268 mosmol/kg in the hypocapnic, eucapnic, and hypercapnic animals, respectively. In a separate group of dogs, water deprivation and water loading studies revealed that sustained hypercapnia does not affect the maximal concentrating or diluting ability of the kidney. We conclude, therefore, that the striking influence of the prevailing PaCO2 on the water-retaining effects of administered vasopressin cannot be ascribed to an altered responsiveness of the nephron per se, but that this influence reflects an alteration in the ease with which the kidney can escape from the antidiuretic effects of this substance.

Download Full-text