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Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin.

ABSTRACT: We have documented recently that bradykinin (BK) directly inhibits activity of the epithelial Na(+) channel (ENaC) via the bradykinin B2 receptor (B2R)-G(q/11)-phospholipase C pathway. In this study, we took advantage of mice genetically engineered to lack bradykinin receptors (B1R, B2R(-/-)) to probe a physiological role of BK cascade in regulation of ENaC in native tissue, aldosterone-sensitive distal nephron. Under normal sodium intake (0.32% Na(+)), ENaC open probability (P(o)) was modestly elevated in B1R, B2R(-/-) mice compared with wild-type mice. This difference is augmented during elevated Na(+) intake (2.00% Na(+)) and negated during Na(+) restriction (<0.01% Na(+)). Saturation of systemic mineralocorticoid status with deoxycorticosterone acetate similarly increased ENaC activity in both mouse strains, suggesting that the effect of BK on ENaC is independent of aldosterone. It is accepted that angiotensin-converting enzyme represents the major pathway of BK degradation. Systemic inhibition of angiotensin-converting enzyme with captopril (30 mg/kg of body weight for 7 days) significantly decreases ENaC activity and P(o) in wild-type mice, but this effect is diminished in B1R, B2R(-/-) mice. At the cellular level, acute captopril (100 ?mol/L) treatment sensitized BK signaling cascade and greatly potentiated the inhibitory effect of 100 nmol/L of BK on ENaC. We concluded that BK cascade has its own specific role in blunting ENaC activity, particularly under conditions of elevated sodium intake. Augmentation of BK signaling in the aldosterone-sensitive distal nephron inhibits ENaC-mediated Na(+) reabsorption, contributing to the natriuretic and antihypertensive effects of angiotensin-converting enzyme inhibition.

SUBMITTER: Mamenko M

PROVIDER: S-EPMC3475746 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin.

Mamenko Mykola M Zaika Oleg O Doris Peter A PA Pochynyuk Oleh O

Hypertension (Dallas, Tex. : 1979) 20121001 5

We have documented recently that bradykinin (BK) directly inhibits activity of the epithelial Na(+) channel (ENaC) via the bradykinin B2 receptor (B2R)-G(q/11)-phospholipase C pathway. In this study, we took advantage of mice genetically engineered to lack bradykinin receptors (B1R, B2R(-/-)) to probe a physiological role of BK cascade in regulation of ENaC in native tissue, aldosterone-sensitive distal nephron. Under normal sodium intake (0.32% Na(+)), ENaC open probability (P(o)) was modestly ...[more]

PMID: 23033373

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Project description:Kidneys play a central role in regulation of potassium homeostasis and maintenance of plasma K+ levels within a narrow physiological range. With-no-lysine (WNK) kinases, specifically WNK1 and WNK4, have been recognized to regulate K+ balance, in part, by orchestrating maxi K+ channel (BK)-dependent K+ secretion in the aldosterone-sensitive distal nephron (ASDN), which includes the connecting tubule and collecting duct. We recently demonstrated that the Ca2+-permeable TRPV4 channel is essential for BK activation in the ASDN. Furthermore, high K+ diet increases TRPV4 activity and expression largely in an aldosterone-dependent manner. In the current study, we aimed to test whether WNK kinases contribute to regulation of TRPV4 activity and its stimulation by aldosterone. Systemic inhibition of WNK with WNK463 (1 mg/kgBW for 3 days) markedly decreased TRPV4-dependent Ca2+ influx in freshly isolated split-opened collecting ducts. Aldosterone greatly increased TRPV4 activity and expression in cultured mpkCCDc14 cells and this effect was abolished in the presence of WNK463. Selective inhibition of WNK1 with WNK-in-11 (400 nM, 24 h) recapitulated the effects of WNK463 on TRPV4-dependent Ca2+ influx. Interestingly, WNK-in-11 did not interfere with up-regulation of TRPV4 expression by aldosterone, but prevented translocation of the channel to the apical plasma membrane. Furthermore, co-expression of TRPV4 and WNK1 into Chinese hamster ovary (CHO) cells increased the macroscopic TRPV4-dependent cation currents. In contrast, over-expression of TRPV4 with a dominant negative WNK1 variant (K233M) decreased the whole-cell currents, suggesting both stimulatory and permissive roles of WNK1 in regulation of TRPV4 activity. Overall, we show that WNK1 is essential for setting functional TRPV4 expression in the ASDN at the baseline and in response to aldosterone. We propose that this new mechanism contributes to regulation of K+ secretion and, by extension, urinary K+ levels to maintain systemic potassium homeostasis.

Project description:BACKGROUND:Whereas genome-wide association study (GWAS) has proven to be an important tool for discovery of variants influencing many human diseases and traits, unfortunately its performance has not been much of all-around success for some complex conditions, for example, hypertension. Because some of the existing effective pharmacotherapeutic agents act by targeting known biological pathways, pathway-based analytical approaches could lead to more success in discovery of disease-associated variants. The objective of the present study was to identify functional variants associated with blood pressure in the aldosterone-regulated sodium reabsorption pathway using the simulated and real blood pressure phenotypes provided for Genetic Analysis Workshop 19. METHODS:The present analysis included 1942 samples with exome sequencing data and for whom blood pressure phenotypes were available. Because only odd-numbered autosomes were available, we restricted analysis to 127 quality-controlled single-nucleotide polymorphisms from the aldosterone-regulated sodium reabsorption pathway. We performed pathway-based association analysis using appropriate regression models for single variant, haplotype and epistasis association analyses. To account for multiple comparisons, statistical significance was empirically derived by permutation procedure and Bonferroni correction. RESULTS:The topmost pathway-based association signals were observed in PRKCA gene for diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) in both real and simulated data. The associations remained significant (P <0.05) after multiple testing corrections for the number of genes. Similarly, the pathway-based 2-locus epistasis analysis indicated significant interactions between INSR and PRKCG for SBP and MAP; INS and PIK3R2 for DBP; PIK3CD and ATP1B2 for hypertension in the real data set. We also observed significant within-gene interactions in INSR for SBP, DBP, and hypertension in the simulated data set. CONCLUSION:The findings from this study show that pathway-based analytical approach targeting known biological pathways can be useful in identification of disease-associated variants that are otherwise undetectable by GWAS. The approach takes advantage of the assumption of nonindependence of variants within and across pathway genes which leads to reduced penalty of multiple testing and thus less-stringent statistical significance threshold.

Dataset Information

Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin.

Publications

Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin.

Similar Datasets

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