The novel circular RNA circG6pc attenuates oxidative stress and mitochondrial damage through miR-7018-5p/Aldh6a1 axis in kidney fibrosis

BACKGROUND: Chronic kidney disease (CKD) is characterized by progressive renal fibrosis, which contributes to disease progression and ultimately leads to kidney failure. Circular RNAs (circRNAs) are key regulators in various fibrotic diseases, showing different expression patterns in different organs. However, the exact role and mechanisms of circRNAs in renal fibrosis are still not fully understood. METHODS: We analyzed circRNA expression in kidney tissues from unilateral ureteral obstruction (UUO) mice using RNA sequencing (RNA-seq). Bioinformatics analysis identified a significant downregulation of circG6pc in fibrotic kidneys. The role and mechanisms by which circG6pc inhibits renal fibrosis were explored both in vivo and in vitro. To further validate our findings, we employed gene overexpression and knockdown, along with immunohistochemistry, dual-luciferase reporter assays, RNA antisense purification (RAP) assays, RNA immunoprecipitation (RIP) assays, western blotting, and RT-qPCR. RESULTS: CircG6pc is significantly downregulated in fibrotic kidneys, and overexpression of circG6pc can notably improve renal fibrosis, mitochondrial dysfunction, and oxidative stress damage. Mechanistically, circG6pc acts as a sponge, directly binding to miR-7018-5p, thereby relieving its inhibitory effect on Aldh6a1 expression. The upregulation of Aldh6a1 promotes mitochondrial biogenesis, corrects mitochondrial dynamics imbalance, alleviates oxidative stress induced by mitochondrial dysfunction, and ultimately suppresses the progression of renal fibrosis. CONCLUSIONS: These findings reveal the molecular mechanism by which circG6pc alleviates mitochondrial dysfunction and oxidative stress through the miR-7018-5p/Aldh6a1 axis, thereby inhibiting renal fibrosis. This provides a potential new strategy for the treatment of progressive CKD.