Inhibition of AMPKα Pathway by Podocyte GOLM1 Exacerbates Diabetic Nephrology in Mice.

Abstract

Inflammation and oxidative stress contribute to diabetic nephrology (DN) progression. Golgi membrane protein 1 (GOLM1) is a Golgi type II transmembrane protein and associates with inflammation and oxidative stress. The present study tries to investigate the role and mechanism of GOLM1 in DN using gain- and loss-of-function approaches. It is found that GOLM1 expression is elevated in diabetic kidneys and high glucose-stimulated podocytes, and positively correlated with renal dysfunction during DN progression. Podocyte-specific GOLM1 ablation prevents, while podocyte-specific GOLM1 overexpression facilitates diabetes-related inflammation, oxidative damage, apoptosis, and renal dysfunction in vivo and in vitro. Mechanistic studies reveal that podocyte-specific GOLM1 ablation attenuated DN through activating adenosine monophosphate activated protein kinase α (AMPKα) pathway, and inhibiting AMPKα pathway completely abolishes the beneficial effects in podocyte-specific GOLM1 knockout (Golm1^pKO) mice or podocytes. Further findings imply that podocyte GOLM1 inactivated AMPKα pathway through interacting with epidermal growth factor receptor to inhibit peroxisome proliferator activated receptor γ. Moreover, treatment with GOLM1 neutralizing antibody is sufficient to alleviate DN in mice. Overall, the study for the first time identifies a pathogenic role of podocyte GOLM1 in the progression of DN, and inhibiting GOLM1 represents an attractive therapeutic approach to treat DN.