AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway.

Abstract

Insulin-like-growth factor-1 (IGF-1) is the ligand for insulin-like growth factor-1 receptor (IGF-1R), and the roles of IGF-1/IGF-1R in diabetic nephropathy (DN) are well-characterized previously. However, the biological functions of AG1024 (an IGF-1R inhibitor) in DN remain unknown. This study investigates the roles and related mechanisms of AG-1024 in DN. The experimental DN was established via intraperitoneal injection of streptozotocin, and STZ-induced diabetic rats were treated with AG1024 (20 mg/kg/day) for 8 weeks. The 24 h proteinuria, blood glucose level, serum creatinine, and blood urea nitrogen were measured for biochemical analyses. The increase in 24 h proteinuria, blood glucose level, serum creatinine, and blood urea of DN rats were conspicuously abated by AG1024. After biochemical analyses, the renal tissue specimens were collected, and as revealed by hematoxylin and eosin staining and Masson staining, AG-1024 mitigated typical renal damage and interstitial fibrosis in DN rats. Then, the anti-inflammatory effect of AG-1024 was assessed by western blotting and ELISA. Mechanistically, AG-1024 upregulated SOCS1 and SOCS3 expression and decreased phosphorylated JAK2, STAT1, and STAT3, as shown by western blotting. Collectively, AG-1024 (an IGF-1R inhibitor) ameliorates renal injury in experimental DN by attenuating renal inflammation and fibrosis via the SOCS/JAK2/STAT pathway.