Targeted inhibition of RGS19 alleviates renal fibrosis by restoring autophagy and modulating immune cell infiltration.

Abstract

Renal fibrosis, a progressive pathological feature of chronic kidney disease (CKD), is driven by impaired autophagic processes and persistent immune activation. The molecular mechanisms that interconnect these pathways remain inadequately understood. This study investigates the role of regulator of G-protein signaling 19 (RGS19), a novel autophagy-associated gene, in the pathogenesis of renal fibrosis. By analyzing transcriptomic data from the Gene Expression Omnibus (GEO) and applying machine learning algorithms, RGS19 was identified as a key fibrosis-related gene. In both in vitro and in vivo renal fibrosis models, we validated its functional role, focusing on autophagic flux and immune responses. We observed that RGS19 expression was elevated in fibrotic kidneys and correlated with increased CD8 + T cell infiltration. Knockdown of RGS19 using siRNA led to reduced p62 accumulation, suppressed rapamycin (p-mechanistic target of rapamycin (mTOR)) activity, and restored LC3B-II levels, reflecting enhanced autophagic flux. Additionally, the secretion of T cell chemoattractants, such as C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10), was diminished. Notably, targeted delivery of RGS19 siRNA via RDYH58 nanoparticles effectively alleviated renal fibrosis in murine models by reducing collagen deposition and immune cell infiltration. These findings suggest that RGS19 plays a central role in linking autophagy dysfunction with immune activation in renal fibrosis and highlight its potential as a therapeutic target for CKD.