Faculty Opinions recommendation of Aldosterone Regulates Pendrin and Epithelial Sodium Channel Activity through Intercalated Cell Mineralocorticoid Receptor-Dependent and -Independent Mechanisms over a Wide Range in Serum Potassium.

BackgroundAldosterone activates the intercalated cell mineralocorticoid receptor, which is enhanced with hypokalemia. Whether this receptor directly regulates the intercalated cell chloride/bicarbonate exchanger pendrin is unclear, as are potassium’s role in this response and the receptor’s effect on intercalated and principal cell function in the cortical collecting duct (CCD).MethodsWe measured CCD chloride absorption, transepithelial voltage, epithelial sodium channel activity, and pendrin abundance and subcellular distribution in wild-type and intercalated cell–specific mineralocorticoid receptor knockout mice. To determine if the receptor directly regulates pendrin, as well as the effect of serum aldosterone and potassium on this response, we measured pendrin label intensity and subcellular distribution in wild-type mice, knockout mice, and receptor-positive and receptor-negative intercalated cells from the same knockout mice.ResultsAblation of the intercalated cell mineralocorticoid receptor in CCDs from aldosterone-treated mice reduced chloride absorption and epithelial sodium channel activity, despite principal cell mineralocorticoid receptor expression in the knockout mice. With high circulating aldosterone, intercalated cell mineralocorticoid receptor gene ablation directly reduced pendrin’s relative abundance in the apical membrane region and pendrin abundance per cell whether serum potassium was high or low. Intercalated cell mineralocorticoid receptor ablation blunted, but did not eliminate, aldosterone’s effect on pendrin total and apical abundance and subcellular distribution.ConclusionsWith high circulating aldosterone, intercalated cell mineralocorticoid receptor ablation reduces chloride absorption in the CCD and indirectly reduces principal cell epithelial sodium channel abundance and function. This receptor directly regulates pendrin’s total abundance and its relative abundance in the apical membrane region over a wide range in serum potassium concentration. Aldosterone regulates pendrin through mechanisms both dependent and independent of the IC MR receptor.

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Faculty Opinions recommendation of Nadph oxidase regulates alveolar epithelial sodium channel activity and lung fluid balance in vivo via O⁻₂ signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13996979.15453086 ◽

2012 ◽

Author(s):

Kenneth Hallows ◽

Mohammad Al-bataineh

Keyword(s):

Nadph Oxidase ◽

Sodium Channel ◽

Fluid Balance ◽

Epithelial Sodium Channel ◽

Channel Activity ◽

Alveolar Epithelial ◽

Lung Fluid ◽

Lung Fluid Balance

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Experimental nephrotic syndrome leads to proteolytic activation of the epithelial sodium channel (ENaC) in the mouse kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00199.2021 ◽

2021 ◽

Author(s):

Bernhard N. Bohnert ◽

Daniel Essigke ◽

Andrea Janessa ◽

Jonas C Schneider ◽

Matthias Wörn ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Sodium Channel ◽

Serine Protease ◽

Cleavage Site ◽

Mineralocorticoid Receptor ◽

Epithelial Sodium Channel ◽

Sodium Retention ◽

Cleavage Sites ◽

Proteolytic Activation ◽

Epithelial Sodium Channel Enac

Proteolytic activation of the renal epithelial sodium channel ENaC involves cleavage events in its α- and γ-subunits and is thought to mediate sodium retention in nephrotic syndrome (NS). However, detection of proteolytically processed ENaC in kidney tissue from nephrotic mice has been elusive so far. We used a refined Western blot technique to reliably discriminate full-length α- and γ-ENaC and their cleavage products after proteolysis at their proximal and distal cleavage sites (designated from the N-terminus), respectively. Proteolytic ENaC activation was investigated in kidneys from mice with experimental NS induced by doxorubicin or inducible podocin deficiency with or without treatment with the serine protease inhibitor aprotinin. Nephrotic mice developed sodium retention and increased expression of fragments of α- and γ-ENaC cleaved at both the proximal and more prominently at the distal cleavage site, respectively. Treatment with aprotinin but not with the mineralocorticoid receptor antagonist canrenoate prevented sodium retention and upregulation of the cleavage products in nephrotic mice. Increased expression of cleavage products of α- and γ-ENaC was similarly found in healthy mice treated with a low salt diet, sensitive to mineralocorticoid receptor blockade. In human nephrectomy specimens, γ-ENaC was found in the full-length form and predominantly cleaved at its distal cleavage site. In conclusion, murine experimental NS leads to aprotinin-sensitive proteolytic activation of ENaC at both proximal and more prominently distal cleavage sites of its α- and γ-subunit, most likely by urinary serine protease activity or proteasuria.

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