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.

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-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 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‐derived adenylyl cyclase 3 or 4 knockout on renal sodium and water excretion and arterial pressure (860.2)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Wararat Kittikulsuth ◽  
Deborah Stuart ◽  
Elena Mironova ◽  
James Stockand ◽  
Donald Kohan
Keyword(s):  
Arterial Pressure ◽  
Adenylyl Cyclase ◽  
Collecting Duct ◽  
Water Excretion

scholarly journals Inhibition of heme oxygenase augments tubular sodium reabsorption

2011 ◽  
Vol 300 (4) ◽  
pp. F941-F946 ◽  
Author(s):  
Keith E. Jackson ◽  
Debra W. Jackson ◽  
Syed Quadri ◽  
Marshall J. Reitzell ◽  
L. Gabriel Navar
Keyword(s):  
Arterial Pressure ◽  
Heme Oxygenase ◽  
Sodium Excretion ◽  
Urine Volume ◽  
Plasma Renin ◽  
Sodium Reabsorption ◽  
Hypertensive Rats ◽  
Water Excretion ◽  
Oxide Synthase ◽  
Water And Sodium Excretion

Heme oxygenase (HO) catalyzes the degradation of heme to form iron, biliverdin, and carbon monoxide (CO). The vascular actions of CO include direct vasodilation of vascular smooth muscle and indirect vasoconstriction through inhibition of nitric oxide synthase (NOS). This study was performed to examine the effects in the kidney of inhibition of heme oxygenase alone or combined with NOS inhibition. Chromium mesoporphyrin (CrMP; 45 μmol/kg ip), a photostable HO inhibitor, was given to control rats and NG-nitro-l-arginine methyl ester (l-NAME)-treated hypertensive rats (50 mg·kg−1·day−1, 12 h, 4 days). In control animals, CrMP decreased CO levels, renal HO-1 levels, urine volume, and sodium excretion, but had no effect on arterial pressure, renal blood flow (RBF), plasma renin activity (PRA), or glomerular filtration rate (GFR). In l-NAME-treated hypertensive rats, CrMP decreased endogenous CO and renal HO-1 levels and had no effect on arterial pressure, RBF, or GFR but decreased sodium and water excretion in a similar manner to control animals. An increase in PRA was observed in untreated rats but not in l-NAME-infused rats, indicating that this effect is associated with an absent NO system. The results suggest that inhibition of HO promotes water and sodium excretion by a direct tubular action that is independent of renal hemodynamics or the NO system.

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.

Acute and chronic actions of bradykinin on renal function and arterial pressure

1985 ◽  
Vol 248 (1) ◽  
pp. F87-F92 ◽  
Author(s):  
J. P. Granger ◽  
J. E. Hall
Keyword(s):  
Arterial Pressure ◽  
Renal Plasma Flow ◽  
Urine Volume ◽  
Plasma Renin ◽  
Urinary Sodium Excretion ◽  
Renal Perfusion ◽  
Acute Effects ◽  
Plasma Aldosterone Concentration ◽  
Control Value ◽  
Renal Vascular

The present study was designed to examine the acute and chronic effects of increased levels of circulating bradykinin (BK) on control of renal hemodynamics, electrolyte excretion, and arterial pressure. Intrarenal infusion of BK (50 ng X kg-1 X min-1) for 60 min in five anesthetized dogs with renal perfusion pressure maintained at a constant level of 108 +/- 1 mmHg had no significant effect on glomerular filtration rate (GFR), whereas it increased renal blood flow (RBF) from a control value of 230 +/- 14 to 282 +/- 18, 266 +/- 15, and 253 +/- 17 ml/min after 15, 30, and 60 min of infusion, respectively. Acute intrarenal infusion of BK also increased urine volume (UV) from 0.255 +/- 0.044 to 0.523 +/- 0.103 ml/min and urinary sodium excretion (UNaV) from 5.72 +/- 1.5 to 13.7 +/- 3.4 mueq/min. To determine whether the potent acute effects of BK on RBF, UV, and UNaV lead to a chronic reduction in arterial pressure, BK (50 ng X kg-1 X min-1) was infused intrarenally for 7 days in conscious dogs. Intrarenal infusion of BK for 7 days had no significant effect on GFR, UNaV, UV, or arterial pressure. However, BK elevated renal plasma flow and decreased renal vascular resistance throughout the 7 days of infusion. Chronic intrarenal BK infusion caused no significant changes in plasma renin activity or plasma aldosterone concentration. Results from these studies indicate that although increased levels of bradykinin in the renal circulation can have potent acute effects on RBF, UV, and UNaV, these effects on UV and UNaV are not sustained and therefore do not result in long-term changes in arterial pressure.

scholarly journals The EP3 receptor regulates water excretion in response to high salt intake

2016 ◽  
Vol 311 (4) ◽  
pp. F822-F829 ◽  
Author(s):  
Shoujin Hao ◽  
AnnMarie DelliPizzi ◽  
Mariana Quiroz-Munoz ◽  
Houli Jiang ◽  
Nicholas R. Ferreri
Keyword(s):  
Tap Water ◽  
Collecting Duct ◽  
Urine Volume ◽  
High Salt ◽  
Whole Body ◽  
Thick Ascending Limb ◽  
Water Excretion ◽  
Water Homeostasis ◽  
Cox 2 ◽  
Ep3 Receptor

The mechanisms by which prostanoids contribute to the maintenance of whole body water homeostasis are complex and not fully understood. The present study demonstrates that an EP3-dependent feedback mechanism contributes to the regulation of water homeostasis under high-salt conditions. Rats on a normal diet and tap water were placed in metabolic cages and given either sulprostone (20 μg·kg−1·day−1) or vehicle for 3 days to activate EP3 receptors in the thick ascending limb (TAL). Treatment was continued for another 3 days in rats given either 1% NaCl in the drinking water or tap water. Sulprostone decreased expression of cyclooxygenase 2 (COX-2) expression by ∼75% in TAL tubules from rats given 1% NaCl concomitant with a ∼60% inhibition of COX-2-dependent PGE2 levels in the kidney. Urine volume increased after ingestion of 1% NaCl but was reduced ∼40% by sulprostone. In contrast, the highly selective EP3 receptor antagonist L-798106 (100 μg·kg−1·day−1), which increased COX-2 expression and renal PGE2 production, increased urine volume in rats given 1% NaCl. Sulprostone increased expression of aquaporin-2 (AQP2) in the inner medullary collecting duct plasma membrane in association with an increase in phosphorylation at Ser269 and decrease in Ser261 phosphorylation; antagonism of EP3 with L-798106 reduced AQP2 expression. Thus, although acute activation of EP3 by PGE2 in the TAL and collecting duct inhibits the Na-K-2Cl cotransporter and AQP2 activity, respectively, chronic activation of EP3 in vivo limits the extent of COX-2-derived PGE2 synthesis, thereby mitigating the inhibitory effects of PGE2 on these transporters and decreasing urine volume.

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