The intercalated cell MR directly regulates pendrin abundance, subcellular distribution and function

Abstract

Aldosterone increases pendrin‐dependent Cl− absorption and HCO3− secretion and activates the intercalated cell (IC) mineralocorticoid receptor (MR) in type B (ICs). Whether the IC MR modulates CCD function and whether aldosterone acts directly on the IC MR in vivo to regulate pendrin in vivo remains to be determined. The purpose of this study was to determine the effect of the IC MR on pendrin abundance, subcellular distribution and function in vivo and to determine if this was from a direct effect of the IC MR. To answer these questions, we developed mice in which MR gene ablation occurred specifically within ICs and measured Cl− absorption in cortical collecting ducts perfused in vitro, pendrin total protein abundance and pendrin subcellular distribution in these IC MR null mice and their wild type littermates. Cl− absorption was ~50% lower in cortical collecting ducts from aldosterone‐treated IC MR null relative to wild type mice. Moreover, following dietary NaCl restriction or an aldosterone infusion, pendrin total protein abundance and pendrin's relative abundance in the apical plasma membrane region were lower in the IC MR null than in wild type littermates. We asked if IC MR gene ablation modulates pendrin abundance and function through a direct effect of the MR within ICs. Since IC MR null mice express both MR positive and negative ICs, we compared pendrin label intensity and pendrin subcellular distribution in MR positive and negative ICs from the same IC MR KO mouse. We observed that pendrin label intensity and pendrin's relative abundance in the apical plasma membrane region were much lower in MR negative than MR positive ICs that were taken from aldosterone‐treated or NaCl‐restricted IC MR null mice. In conclusion, IC MR gene ablation reduces Cl− absorption in the CCD. Furthermore, IC MR gene ablation reduces pendrin total protein abundance and pendrin abundance in the region of the apical plasma membrane through a direct effect of the MR within ICs.Support or Funding InformationSusan M. Wall, M.D.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.