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

2016 ◽  
Vol 311 (5) ◽  
pp. F1074-F1083 ◽  
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.

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

2014 ◽  
Vol 306 (6) ◽  
pp. F597-F607 ◽  
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.

Role of prostaglandins in collecting duct-derived endothelin-1 regulation of blood pressure and water excretion

2007 ◽  
Vol 293 (6) ◽  
pp. F1805-F1810 ◽  
Author(s):  
Yuqiang Ge ◽  
Kevin A. Strait ◽  
Peter K. Stricklett ◽  
Tianxin Yang ◽  
Donald E. Kohan
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Urine Volume ◽  
Mrna Levels ◽  
Water Excretion ◽  
Salt Loading ◽  
Endothelin 1 ◽  
Cox 2 ◽  
Cox 1

Collecting duct (CD)-derived endothelin-1 (ET-1) exerts natriuretic, diuretic, and hypotensive effects. In vitro studies have implicated cyclooxygenase (COX) metabolites, and particularly PGE2, as important mediators of CD ET-1 effects. However, it is unknown whether PGE2 mediates CD-derived ET-1 actions in vivo. To test this, CD ET-1 knockout (KO) and control mice were studied. During normal salt and water intake, urinary PGE2 excretion was unexpectedly increased in CD ET-1 KO mice compared with controls. Salt loading markedly increased urinary PGE2 excretion in both groups of mice; however, the levels remained relatively higher in KO animals. Acutely isolated inner medullary collecting duct (IMCD) from KO mice also had increased PGE2 production. The increased IMCD PGE2 was COX-2 dependent, since NS-398 blocked all PGE2 production. However, increased CD ET-1 KO COX-2 protein or mRNA could not be detected in inner medulla or IMCD, respectively. Inner medullary COX-1 mRNA and protein levels and IMCD COX-1 mRNA levels were unaffected by Na intake or CD ET-1 KO. KO mice on a normal or high-Na diet had elevated blood pressure compared with controls; this difference was not altered by indomethacin or NS-398 treatment. However, indomethacin or NS-398 did increase urine osmolality and reduce urine volume in KO, but not control, animals. In summary, IMCD COX-2-dependent PGE2 production is increased in CD ET-1 KO mice, indicating that CD-derived ET-1 is not a primary regulator of IMCD PGE2. Furthermore, the increased PGE2 in CD ET-1 KO mice partly compensates for loss of ET-1 with respect to maintaining urinary water excretion, but not in blood pressure control.

Abstract 308: Nephron Specific Deletion Of Angiotensinogen Modulates Blood Pressure

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Matias Calquin ◽  
Shuping Wang ◽  
Fumio Niimura ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Proximal Tubule ◽  
Urine Volume ◽  
Plasma Renin ◽  
Urine Osmolality ◽  
Metabolic Balance ◽  
Salt Diet ◽  
Plasma Renin Concentration ◽  
Specific Deletion

It is unknown if intrarenal generation of angiotensinogen (AGT) is important in blood pressure (BP) regulation. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, while proximal tubule-specific deletion of AGT using the KAP promoter-Cre transgene did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron-wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP flanked AGT alleles to achieve nephron-specific AGT disruption after doxycycline induction. Adult Pax8-rtTA/LC-1/floxed AGT mice at 3 months of age were treated with doxycycline 2 mg/ml in drinking water for 11 days and studied 4 weeks after treatment. Blood pressure (recorded via telemetry) and metabolic balance studies were determined during 5 days of normal, high and low Na diets. Compared to controls, AGT knockout (KO) mice demonstrated significantly lower systolic, diastolic, and mean BPs on all three diets (N=4 each group). The BP reduction was most evident on a low Na diet (mean BP 107 ± 2 mmHg in controls and 88 ± 13 mmHg in AGT KO). Plasma renin concentration was higher in the AGT KO mice as compared to controls on all three diets. There were no detectable differences in weight, urine volume, urine osmolality or urine Na excretion between the controls and KO mice on all three diets, however due to variability, small differences in these parameters may not have been detected. Taken together, these data suggest that nephron AGT may contribute to BP regulation and this is most evident during low Na intake.

Role of the renin–angiotensin–aldosterone system in collecting duct-derived endothelin-1 regulation of blood pressureThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

2008 ◽  
Vol 86 (6) ◽  
pp. 329-336 ◽  
Author(s):  
Yuqiang Ge ◽  
Yufeng Huang ◽  
Donald E. Kohan
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Similar Degree ◽  
Water Excretion ◽  
Renin Angiotensin ◽  
Endothelin 1 ◽  
And Control ◽  
Renin Content

Renal collecting duct (CD)-specific knockout of endothelin-1 (ET-1) causes hypertension and impaired Na excretion. A previous study noted failure to suppress the renin–angiotensin–aldosterone axis in these knockout (KO) mice, hence the current investigation was undertaken to examine the role of this system in CD ET-1 KO. Renal renin content was similar in kidneys from CD ET-1 KO and control mice during normal Na intake; high-Na intake suppressed renal renin content to a similar degree in KO and control. Plasma renin concentrations paralleled changes in renal renin content. Valsartan, an angiotensin receptor blocker (ARB), abolished the hypertension in CD ET-1 KO mice during normal Na intake. High-Na intake + ARB treatment increased blood pressure in CD ET-1 KO, but not in controls. High-Na intake was associated with reduced Na excretion in CD ET-1 KO animals, but no changes in water excretion or creatinine clearance were noted. Spironolactone, an aldosterone antagonist, also normalized blood pressure in CD ET-1 KO mice during normal Na intake, whereas high-Na intake + spironolactone raised blood pressure only in CD ET-1 KO animals. In summary, hypertension in CD ET-1 KO is partly due to angiotensin II and aldosterone. We speculate that CD-derived ET-1 may regulate, via a novel pathway, renal renin production.

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

2018 ◽  
Vol 315 (3) ◽  
pp. F607-F617 ◽  
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.

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

2012 ◽  
Vol 302 (1) ◽  
pp. F78-F84 ◽  
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.

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

2015 ◽  
Vol 309 (1) ◽  
pp. F48-F56 ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Matias Calquin ◽  
Syed Quadri ◽  
Shuping Wang ◽  
...  
Keyword(s):  
Water Intake ◽  
Gene Knockout ◽  
Collecting Duct ◽  
Urine Volume ◽  
Plasma Osmolality ◽  
Renin Angiotensin System ◽  
Urine Osmolality ◽  
Water Restriction ◽  
Water Excretion ◽  
Prorenin Receptor

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.

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

2004 ◽  
Vol 287 (4) ◽  
pp. F797-F805 ◽  
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.

Effect of alcohol withdrawal on blood pressure, plasma renin activity, aldosterone, cortisol and dopamine β-hydroxylase

1984 ◽  
Vol 66 (6) ◽  
pp. 659-663 ◽  
Author(s):  
L. T. Bannan ◽  
J. F. Potter ◽  
D. G. Beevers ◽  
J. B. Saunders ◽  
J. R. F. Walters ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Renin Activity ◽  
Alcohol Withdrawal ◽  
Diastolic Pressure ◽  
Urine Volume ◽  
Plasma Renin ◽  
Renin Activity ◽  
Withdrawal Symptoms ◽  
Urinary Volume ◽  
Blood Pressures

1. Sixty-five alcoholic patients admitted for detoxification had blood pressure, withdrawal symptoms, plasma cortisol (PC) and plasma aldosteron (PA) levels, plasma renin activity (PRA), and serum dopamin β-hydroxylase (DBH) levels measured on the first and fourth days after admission. 2. On the morning after admission blood pressure was elevated (>140/90) in 32 patients (49%) and was 160/95mmHg or more in 21 (32%). PRA was initially elevated in 41 patients, PA levels in 14, and 13 patients had raised PC levels. By the fourth day, blood pressure and bio-chemical measures had fallen significantly while urine volume and sodium output, low on admission, had increased significantly. On admission urinary metanephrine levels were raised in four out of the 31 patients who had them measured. 3. The height of both the systolic and diastolic blood pressures was significantly related to the severity of the alcohol. withdrawal symptoms. Of the biochemical parameters measured, PC level correlated with systolic but not diastolic pressure, and urinary volume was inversely correlated with the height of the diastolic pressure. No relationship was found between blood pressure and PRA or PA level. 4. The pressor effect of alcohol withdrawal could be due to sympathetic nervous system overactivity, or possibly to hypercortisolaemia. The first hypothesis seems more likely.

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