Abstract
Renal fibrosis is a long-term and progressively worsening condition that impacts kidney function during aging and in the context of chronic kidney disease (CKD). CKD and renal fibrosis affect approximately 10% of the global population and are prevalent in about half of individuals over the age of 70. Despite ongoing research, the mechanisms underlying renal fibrosis are still not well understood, and there is currently a lack of effective treatments available. In the present study, we demonstrated a significant increase of circPWWP2A in renal tubular cells both in vivo and in vitro models of renal fibrosis. Suppressing circPWWP2A has the potential to reduce mitochondrial dysfunction and the production of mitochondrial reactive oxygen species (mtROS), ultimately leading to the inhibition of renal fibrosis. Whereas, supplementation of circPWWP2A led to more serve mitochondrial dysfunction, mtROS production and renal fibrosis. Mechanistically, we found the expression of circPWWP2A was negatively correlated with the expression of miR-182. And we further confirmed miR-182 was the direct target of circPWWP2A by dual-luciferase reporter assay and RIP assay. Then, we found miR-182 suppressed the expression of ROCK1 in both in vitro and in vivo models of renal fibrosis. Luciferase microRNA target reporter assay further indicated ROCK1 as a direct target of miR-182. Knockdown of ROCK1 inhibits renal fibrosis and mitochondrial dysfunction, suggesting ROCK1 not only served as an injurious role in mitochondrial homeostasis but also a pro-fibrotic factor in CKD. Taking together, our findings suggest that circPWWP2A may promote renal interstitial fibrosis by modulating miR-182/ROCK1-mediated mitochondrial dysfunction.