The pathogenic role of Succinate-SUCNR1: A critical function that induces renal fibrosis via infiltration of M2 macrophage

Abstract

Abstract Background Renal fibrosis is a major determinant of progressive loss of kidney function in chronic kidney disease (CKD), and alternatively activated M2 macrophages play an essential role in the progression. Serum succinate level is consistently elevated in diabetes and obesity, and diabetes and obesity are critical causes of CKD, but whether elevated succinate can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis is undetermined. Methods Male C57/BL6 mice were fed with special water (supplement with 4% succinate) for 12 weeks to evaluate the effects on renal interstitial fibrosis, and depletion of macrophages by clodronate liposomes was adopted to validate the importance of macrophages in vivo. We further used RAW 264.7 and NRK-49F cells to explore the underlying molecular mechanisms. Results Succinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3β/β-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells. Conclusions The causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages, and succinate-SUCNR1 was involved in activating p-Akt/p-GSK3β/β-catenin, CTGF expression and the crosstalk between the macrophages and fibroblasts. Our findings provide a promising strategy for preventing metabolic CKD progress by promoting urine succinate excretion and/or employing selective antagonists for SUCNR1.