The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion - Conference Presentation

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 (MRko 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 MRko mice need NaCl supplementation
to thrive, adult MRko 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
MRko 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 MRko 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.