Renal adaptation to primary aldosteronism requires GDF15 to control plasma potassium level in mice and human.

Abstract

Background Primary aldosteronism (PA), the most common secondary cause of hypertension, results from autonomous aldosterone production, driving renal Na retention and K secretion. Paradoxically, only 9 to 37% of PA patients develop hypokalemia, suggesting adaptive mechanisms. Growth differentiation factor 15 (GDF15) promotes intercalated cell type A (ICA) proliferation and K reabsorption in the collecting duct, but its role in PA is unexplored. Methods We measured urinary and plasma GDF15 in 81 PA patients (two centers) and 41 controls. A murine model of chronic mineralocorticoid excess (DOCP treatment) was used in wild-type (WT) and GDF15 knockout (GDF15KO) mice to assess renal adaptation. Results PA patients exhibited 3-fold higher urinary GDF15 and 1.6-fold higher plasma GDF15 than controls, with normalization post-treatment. 24-hour urinary GDF15 correlated with urinary aldosterone (rho=0.35, p<0.01), age, and BMI (Body Mass Index), but not plasma K. WT mice developed hypokalemia following DOCP administration (plasma K 3.5{+/-}0.1 mM vs. 4.3{+/-}0.1 mM in controls, p<0.01). In GDF15KO mice DOCP-induced hypokalemia was more severe, indicating a protective role of GDF15. In WT mice, DOCP increased 24-hour urinary GDF15 (2-fold) and GDF15 expression in the collecting duct. Transcriptomic analysis revealed an inverted transcriptional response to chronic mineralocorticoid in ICA and PC according to the genotype. This could be related to the increase of ICA number in WT, an effect abolished in GDF15KO mice. Conclusions These results indicate that GDF15 is involved in the renal response to mineralocorticoid excess, likely through stimulation of ICA proliferation, which may promote potassium reabsorption in the collecting duct and help mitigate aldosterone-mediated K loss.