Targeting interferon regulatory factor 7 alleviates renal fibrosis by inhibiting macrophage-to-myofibroblast transition

Abstract

The development of effective therapeutic strategies for renal fibrosis is a key centerpiece in addressing the progression of Chronic Kidney Disease (CKD) to end-stage renal disease (ESRD). Macrophage-to-myofibroblast transition (MMT) is thought to exacerbate the progression of renal fibrosis. Therefore, targeting MMT may be a promising therapeutic strategy for treating renal fibrosis. This study aimed to identify the key effector molecules and specific mechanisms of MMT in renal fibrosis and to provide new ideas for developing drugs for treating renal fibrosis. Analysis of transcriptomic data from Renal interstitial fibrosis (RIF) patients showed that Interferon regulatory factor 7 (IRF7) plays an important role in MMT. Further, the unilateral ureteral obstruction (UUO) model established in IRF7 knockout mice and the MMT model established in IRF7 deficiency macrophage, respectively, found that IRF7 was able to promote MMT by regulating the transcriptional activation of Cathepsin S (CTSS), increasing the number of myofibroblasts, leading to a persistent production of extracellular matrix (ECM) and ultimately exacerbating renal fibrosis. This process is dependent on the regulation of the TGF-β/Smad3 signaling pathway. In addition, we found that human umbilical cord mesenchymal stem cell-derived exosomes mimetic extracellular nanovesicles treatment of renal fibrosis may similarly depend on IRF7-mediated MMT to function. In conclusions, in renal fibrosis, upregulation of IRF7 expression depends on the regulation of the TGF-β/Smad3 signaling pathway and exacerbates renal fibrosis by regulating MMT through the IRF7-CTSS axis. These mechanisms suggest that targeting IRF7 may be the key to future treatment of renal fibrosis.