The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling.

Abstract

Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal mineralocorticoid receptor antagonist finerenone or selective myeloid mineralocorticoid receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice. This protection was associated with increased expression of M2-antiinflamatory markers in macrophages from finerenone-treated or myeloid mineralocorticoid receptor-deficient mice. Moreover, the inflammatory population of CD11b⁺, F4/80⁺, Ly6C^high macrophages was also reduced. Mineralocorticoid receptor inhibition promoted increased IL-4 receptor expression and activation in the whole kidney and in isolated macrophages, thereby facilitating macrophage polarization to an M2 phenotype. The long-term protection conferred by mineralocorticoid receptor antagonism was also translated to the Large White pig pre-clinical model. Thus, our studies support the rationale for using mineralocorticoid receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.