RIG-I aggravates interstitial fibrosis via c-Myc-mediated fibroblast activation in UUO mice

Progressive tubulointerstitial fibrosis is the common final outcome for all kidney diseases evolving into chronic kidney disease (CKD), whereas molecular mechanisms driving fibrogenesis remain elusive. Retinoic acid-inducible gene-I (RIG-I), an intracellular pattern recognition receptor, is originally identified participating in immune response by recognizing virus RNA. Here, we revealed for the first time that RIG-I was induced in unilateral ureteral obstruction (UUO) and folic acid (FA) renal fibrosis models and moderate-degree renal fibrosis patients. Besides, we found RIG-I was mainly located in renal tubular epithelial cells and promoted the production and release of inflammatory cytokines, such as interleukin (IL)-1 beta and IL-6 through activation of NF-kappa B. Inflammatory cytokines released by tubular epithelial cells activated c-Myc-mediated TGF-beta/Smad signaling in fibroblasts, which in turn aggravated interstitial fibrosis by promoting fibroblast activation and production of extracellular matrix components (ECM). Deficiency of RIG-I attenuated renal fibrosis by the regulation of inflammatory responses, c-Myc expression, and fibroblast activation. Besides, gene silencing of RIG-I reduced inflammatory cytokines in cultured tubular epithelial cells treated with Angiotensin II. Knockdown of c-Myc or c-Myc inhibitor blocked IL-1 beta-induced fibroblast activation. Collectively, our study demonstrates that RIG-I plays a significant role in the progress of renal fibrosis via regulating c-Myc-mediated fibroblast activation. Key messages center dot RIG-I was constantly elevated in kidneys from renal fibrotic mice. center dot RIG-I facilitated inflammatory cytokine production in tubular epithelial cells. center dot RIG-I aggravated renal fibrosis via c-Myc-mediated TGF-beta/Smad activation.