High chloride induces aldosterone resistance in the distal nephron.

Aim: Increasing the dietary intake of K⁺ in the setting of a high salt intake promotes renal Na⁺ excretion even though K⁺ concurrently enhances the secretion of aldosterone, the most effective stimulus for renal Na⁺ reabsorption. Here, we questioned whether in the high salt state a mechanism exists, which attenuates the aldosterone response to prevent renal Na⁺ reabsorption after high K⁺ intake.

Methods: Mice were fed diets containing varying amounts of Na⁺ combined with KCl or KCitrate. Murine cortical connecting duct (mCCDcl1) cells were cultured in media containing normal or high [Cl^-]. The response to aldosterone was analyzed by high-resolution imaging and by biochemical approaches.

Results: The canonical cellular response to aldosterone, encompassing translocation of the mineralocorticoid receptor (MR) and activation of the epithelial Na⁺ channel ENaC was repressed in Na⁺-replete mice fed a high KCl diet, even though plasma aldosterone concentrations were increased. The response to aldosterone was restored in Na⁺-replete mice when the extracellular [Cl^-] increase was prevented by feeding a high KCitrate diet. In mCCDcl1 cells, an elevated extracellular [Cl^-] was sufficient to disrupt the aldosterone-induced MR translocation.

Conclusion: These findings indicate a pivotal role for extracellular [Cl^-] in modulating renal aldosterone signaling to adapt MR activation by a high K⁺ intake to the NaCl balance. An impairment of [Cl^-]-mediated aldosterone resistance may contribute to excessive MR activation by aldosterone in the presence of a high salt intake characteristic of the Western diet, resulting in an inappropriate salt reabsorption and its downstream detrimental effects.