Premium
The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion
Author(s) -
Czogalla Jan,
Vohra Twinkle,
Ribas David Penton,
Kirschmann Moritz,
Carrel Monique,
Loffing Johannes
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1223.1
Subject(s) - distal convoluted tubule , mineralocorticoid receptor , reabsorption , epithelial sodium channel , endocrinology , aldosterone , medicine , mineralocorticoid , pendrin , cotransporter , kidney , receptor , renal sodium reabsorption , chemistry , convoluted tubule , renal physiology , biology , sodium , transporter , biochemistry , organic chemistry , gene
The mineralocorticoid receptor (MR) and its ligand aldosterone increase renal sodium reabsorption via regulation of the epithelial Na + channel (ENaC) and the Na‐K‐ATPase in the renal collecting system. Previous studies suggested that aldosterone also regulates the thiazide‐sensitive cotransporter in the renal distal convoluted tubule (DCT). However, whether aldosterone directly regulates NCC via MR, or indirectly through systemic alterations such as changed plasma potassium, remained controversial. We have now generated a mouse model carrying a targeted deletion of MR in ~16% of cells randomly scattered along the renal tubule (MR ko mice). In this model, MR‐positive and MR‐negative cells can be studied next to each other in the same physiological context via immunofluorescence. To evaluate microscope images objectively, we further developed an ImageJ script allowing radial quantification of optical density, thus allowing comparison of apical staining intensities. Although newborn MR ko mice need NaCl supplementation to thrive, adult MR ko do not show any differences to wildtype littermates in terms of general physiology, mRNA and protein expression of renal ion transport proteins and urine concentrating capacity, under both normal and low salt diet. MR‐negative cells in the renal collecting system of MR ko mice do not show any detectable alphaENaC expression, while gammaENaC is diffusely distributed over the cytoplasm. In MR‐positive cells, these ENaC subunits are targeted to the apical cell surface. Although dietary Na + restriction increases NCC abundance and phosphorylation to a similar extent in control and MR ko mice, no differences in NCC regulation were observed between MR‐negative and MR‐positive DCT cells. In conclusion, MR is crucial for ENaC regulation but dispensable for the maintenance of NCC expression and phosphorylation under control conditions and for NCC upregulation in response to dietary Na + restriction. Support or Funding Information This work was supported by a collaborative project grant from the Zurich Center for Integrative Human Physiology (ZIHP), research funds from the Swiss National Center for Competence in Research “Kidney.CH” and by a project grant (310030_143929/1) from the Swiss National Science Foundation.