Increased severity of chronic kidney disease in response to high potassium intake is dependent on mineralocorticoid receptor activation

Olivier, V.; Arnoux, G.; Ramakrishnan, S.; SASSI, A.; Roth, I.; Chassot, A.; Tournier, M.; Dizin, E.; Hummler, E.; Rutkowski, J.; Feraille, E.

doi:10.1101/2022.06.15.496280

bioRxiv · 10.1101/2022.06.15.496280

Increased severity of chronic kidney disease in response to high potassium intake is dependent on mineralocorticoid receptor activation

Olivier, V.·Arnoux, G.·Ramakrishnan, S.·SASSI, A.·Roth, I.·Chassot, A.·Tournier, M.·Dizin, E.·Hummler, E.·Rutkowski, J.·Feraille, E.

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Abstract

Dietary treatment is seminal for management of chronic kidney disease (CKD). The aim of our project was to assess the effects of potassium intake on the progression of CKD. We used 2 mouse CKD models to analyze the effects of potassium intake on CKD : the unilateral ureteral obstruction (UUO) and the POD-ATTAC models. POD-ATTAC mice display a podocyte-specific apoptosis after the administration of a chemical inducer. We also studied the effect of mineralocorticoid receptor (MR) using UUO in kidney tubule-specific MR knockout mice. In both UUO and POD-ATTAC mice, high potassium diet increased interstitial fibrosis. High potassium diet also increased the abundance of the extracellular matrix protein fibronectin and decreased the abundance of the epithelial marker Na+-K+ ATPase. Consistently, POD-ATTAC mice fed with high potassium diet displayed lower glomerular filtration rate. Spironolactone, a MR antagonist, decreased fibrosis induced by high potassium diet in POD-ATTAC mice. However, kidney tubule-specific MR knockout did not improve the fibrotic lesions induced by UUO under normal or high potassium diets. Macrophages from high potassium-fed POD-ATTAC mice displayed higher mRNA levels of the pro-inflammatory chemokine MCP1. This effect was decreased by spironolactone, suggesting a role of MR signaling in myeloid cells in the pro-fibrotic effect of potassium-rich diet. High potassium intake generates more fibrosis leading to decreased kidney function in experimental CKD. MR signaling plays a pivotal role in this potassium-induced fibrosis. The effect of reducing potassium intake on CKD progression should be assessed in future clinical trials. Translational statementDietetic approach is a cheap and effective therapy to slow down the development of chronic kidney diseases and kidney fibrosis. Potassium-rich diets are protective against renal and cardiovascular events in the general population, albeit some conflicting data were obtained in patients with chronic kidney disease. We showed that potassium-rich diet accelerates fibrosis development, by enhancing kidney inflammation in two mouse models of chronic kidney disease. These data suggest that potassium-rich diets should not be advised in patients with chronic kidney disease, unless future clinical trials demonstrate any beneficial effect in these patients.

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Olivier, V., Arnoux, G., Ramakrishnan, S., SASSI, A., Roth, I., Chassot, A., Tournier, M., Dizin, E., Hummler, E., Rutkowski, J., Feraille, E.. 2022-06-17. Increased severity of chronic kidney disease in response to high potassium intake is dependent on mineralocorticoid receptor activation. https://doi.org/10.1101/2022.06.15.496280

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