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.