NCOA1 Attenuates High Glucose-Induced Mesangial Matrix Expansion Through ITGA5 Inhibition

To investigate whether nuclear receptor coactivator 1 (NCOA1) participates in the pathogenesis of diabetic kidney disease (DKD) by modulating extracellular matrix (ECM) production in mesangial cells (MCs), and to explore the underlying molecular mechanism.

The rat glomerular MCs and streptozotocin-induced DKD mouse models were employed. NCOA1 expression was evaluated under both normal and high-glucose conditions. The functional role of NCOA1 was assessed via plasmid-mediated overexpression in high-glucose treated MCs. Integrin alpha 5 (ITGA5) expression was examined in vivo and in vitro, and its regulatory relationship with NCOA1 was investigated. Furthermore, siRNA-mediated knockdown of ITGA5 was performed to determine its necessity in high-glucose driven ECM overproduction.

NCOA1 was abundantly expressed in resting MCs but markedly downregulated upon high-glucose stimulation. Plasmid-driven overexpression of NCOA1 significantly attenuated high-glucose induced ECM protein synthesis. Notably, ITGA5 expression was substantially elevated in the glomerular mesangium of DKD mice and in high-glucose exposed MCs, and this upregulation was negatively governed by NCOA1. Functionally, ITGA5 silencing effectively abrogated the excessive matrix production provoked by high glucose, phenocopying the protective effect of NCOA1 overexpression.

NCOA1 protects against high-glucose induced mesangial expansion in DKD, at least partially, through negative regulation of ITGA5. These findings identify the NCOA1/ITGA5 axis as a potential therapeutic target for counteracting glomerular fibrosis in DKD.