IGF-1/IGF-1R blockade ameliorates diabetic kidney disease through normalizing Snail1 expression in a mouse model

Rong Dong, Jiali Yu, Funxun Yu, Song Yang, Qi Qian, Yan Zha
2019 American Journal of Physiology. Endocrinology and Metabolism  
This study investigated the role of insulin-like growth factor-1/insulin-like growth factor-1 receptor (IGF-1/IGF-1R) in the genesis and progression of diabetic kidney disease (DKD) in a streptozocin (STZ)-induced mouse diabetes model. We show elevated IGF-1 expression in the DKD kidneys after 16 weeks of diabetic onset. Intraperitoneal administration of IGF-1R inhibitor (GSK4529) from weeks 8 to 16 post-diabetes induction ameliorated urinary albumin excretion and kidney histological changes
more » ... to diabetes, including amelioration of glomerulomegaly, inflammatory infiltration, and tubulointerstitial fibrosis. The GSK4529 treatment also attenuated alterations in renal tubular expressions of E-cad1 and matrix protein fibronectin. Moreover, renal fibrosis in DKD (without treatment) was associated with Snail1 overexpression that was effectively prevented by IGF-1R inhibition. Further experiments in cultured renal epithelial cells (NRK-52E) showed that IGF-1 silencing reproduced in vivo effects of IGF-1R inhibition with markedly attenuated Snail1 expression and nearly normalization of the Ecad1 and fibronectin expression pattern. Further Snail1 silencing prevented high-glucose induced changes without affecting IGF-1 expression, consistent with Snail1 acting downstream to IGF-1. The antifibrotic effects were also shown with benazepril or insulin treatment but to a much lesser degree. In summary, in STZ-induced diabetic mice, activation of IGF-1 in diabetic kidneys induces fibrogenesis through Snail1 upregulation. The diabetic related histological and functional changes, as well as fibrogenesis, can be attenuated by IGF-1/IGF-1R inhibition.
doi:10.1152/ajpendo.00071.2019 pmid:31361542 fatcat:xbcb5zrkhjdxrdhq3iwatsw4lm