Aldosterone mediates potassium-induced kidney fibrosis through tubular and mesenchymal mineralocorticoid receptor activation

Abstract

Background Mineralocorticoid receptor (MR) activation drives chronic kidney disease (CKD) progression, as evidenced by the renoprotective effects of MR antagonists in clinical trials and conditional knockout models in myeloid and vascular smooth muscle cells. Dietary potassium stimulates aldosterone secretion, yet its impact on renal fibrosis, a hallmark of CKD progression, has not been systematically investigated. We hypothesised that high dietary potassium promotes renal fibrosis through aldosterone-driven MR activation, and sought to identify the renal cell populations mediating this effect. Methods Renal fibrosis was evaluated in two murine models: unilateral ureteral obstruction (UUO, days 7-10) and inducible podocyte apoptosis (day 20), across dietary potassium concentrations ranging from 0.01% to 2%. GFR was measured by transcutaneous FITC-sinistrin clearance. Fibrosis was assessed by histology, immunofluorescence, and biochemistry. The MR dependence of the potassium effect was tested pharmacologically using finerenone and genetically using tissue-specific conditional knockout of MR in renal tubular epithelial and mesenchymal cells. Results High dietary potassium increased renal fibrosis in both models and reduced GFR by a further 50% in the podocyte apoptosis model. The pro-fibrotic effect persisted across sodium and anion variants, supporting specificity to potassium per se. Fibrosis burden correlated logarithmically with plasma aldosterone, and the pro-fibrotic effect of high potassium was attenuated by finerenone. Conditional MR deletion in tubular epithelial and mesenchymal cells independently recapitulated this protection, establishing cell-type specificity of the pathway. Conclusion High dietary potassium worsens renal fibrosis in murine models through aldosterone-dependent MR activation. This study provides the first in vivo genetic evidence that MR activation in renal tubular epithelial and mesenchymal cells can drive fibrosis, identifying a potentially actionable pathway in CKD management.