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Angiotensin II increases activity of the ClC-K2 Cl^- channel in collecting duct intercalated cells by stimulating production of reactive oxygen species.

ABSTRACT: The renal collecting duct plays a critical role in setting urinary volume and composition, with principal cells transporting Na⁺ and K⁺ and intercalated cells mediating Cl^- reabsorption. Published evidence implies Angiotensin II (Ang II) is a potent regulator of the collecting duct apical transport systems in response to systemic volume depletion. However, virtually nothing is known about Ang II actions on the basolateral conductance of principal and intercalated cells. Here, we combined macroscopic and single channel patch clamp recordings from freshly isolated mouse collecting ducts with biochemical and fluorescence methods to demonstrate an acute stimulation of the basolateral Cl^- conductance and specifically the ClC-K2 Cl^- channel by nanomolar Ang II concentrations in intercalated cells. In contrast, Ang II did not exhibit measurable effects on the basolateral conductance and on K_ir4.1/5.1 potassium channel activity in principal cells. Although both Ang II receptors AT₁ and AT₂ are expressed in collecting duct cells, we show that AT₁ receptors were essential for stimulatory actions of Ang II on ClC-K2. Moreover, AT₁R^-/- mice had decreased renal ClC-K2 expression. We further demonstrated that activation of NADPH oxidases is the major signaling pathway downstream of Ang II-AT₁R that leads to stimulation of ClC-K2. Treatment of freshly isolated collecting ducts with Ang II led to production of reactive oxygen species on the same timescale as single channel ClC-K2 activation. Overall, we propose that Ang II-dependent regulation of ClC-K2 in intercalated cells is instrumental for stimulation of Cl^- reabsorption by the collecting duct, particularly during hypovolemic states.

SUBMITTER: Khayyat NH

PROVIDER: S-EPMC7949157 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Retinoic acid is the bioactive derivative of vitamin A, which plays an indispensible role in kidney development by activating retinoic acid receptors. Although the location, concentration and roles of endogenous retinoic acid in post-natal kidneys are poorly defined, there is accumulating evidence linking post-natal vitamin A deficiency to impaired renal concentrating and acidifying capacity associated with increased susceptibility to urolithiasis, renal inflammation and scarring. The aim of this study is to examine the presence and the detailed localization of endogenous retinoic acid activity in neonatal, young and adult mouse kidneys, to establish a fundamental ground for further research into potential target genes, as well as physiological and pathophysiological roles of endogenous retinoic acid in the post-natal kidneys. METHODOLOGY/PRINCIPAL FINDINGS:RARE-hsp68-lacZ transgenic mice were employed as a reporter for endogenous retinoic acid activity that was determined by X-gal assay and immunostaining of the reporter gene product, ?-galactosidase. Double immunostaining was performed for ?-galactosidase and markers of kidney tubules to localize retinoic acid activity. Distinct pattern of retinoic acid activity was observed in kidneys, which is higher in neonatal and 1- to 3-week-old mice than that in 5- and 8-week-old mice. The activity was present specifically in the principal cells and the intercalated cells of the collecting duct system in all age groups, but was absent from the glomeruli, proximal tubules, thin limbs of Henle's loop and distal tubules. CONCLUSIONS/SIGNIFICANCE:Endogenous retinoic acid activity exists in principal cells and intercalated cells of the mouse collecting duct system after birth and persists into adulthood. This observation provides novel insights into potential roles for endogenous retinoic acid beyond nephrogenesis and warrants further studies to investigate target genes and functions of endogenous retinoic acid in the kidney after birth, particularly in the collecting duct system.

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Angiotensin II increases activity of the ClC-K2 Cl^- channel in collecting duct intercalated cells by stimulating production of reactive oxygen species.

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Angiotensin II increases activity of the ClC-K2 Cl- channel in collecting duct intercalated cells by stimulating production of reactive oxygen species.

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OmicsDI is part of the ELIXIR infrastructure

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Angiotensin II increases activity of the ClC-K2 Cl^- channel in collecting duct intercalated cells by stimulating production of reactive oxygen species.