RIPK3 blockade attenuates kidney fibrosis in a folic acid model of renal injury.

Abstract

Renal fibrosis is common to all forms of progressive kidney disease. However, current therapies to limit renal fibrosis are largely ineffective. Phosphorylation of receptor-interacting serine/threonine-protein kinase (RIPK) 3 has been recently suggested to be a key regulator of the pyrin domain containing 3 (NLRP3) inflammasome, which provides new insights into mechanisms of chronic kidney disease (CKD). However, the specific effect of RIPK3 on renal cortical fibrosis has not been fully understood. To study the function of RIPK3, both genetic ablation and pharmacological inhibition of RIPK3 (dabrafenib) were used in the study. Our studies identify that RIPK3 promotes renal fibrosis via the activation of the NLRP3 inflammasome in a mouse model of folic acid-induced nephropathy. Both interventional strategies decreased the renal fibrotic response, and beneficial effects converged on the NLRP3 inflammasome. This study demonstrates a role for RIPK3 as the mediator of renal fibrosis via the upregulation of inflammasome activation. Dabrafenib, as an inhibitor of RIPK3, may be an effective treatment to limit the progression of the tubulointerstitial fibrosis.