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