HGF alleviates high glucose-induced injury in podocytes by GSK3β inhibition and autophagy restoration

Abstract

Podocyte injury or loss plays a major role in the pathogenesis of proteinuric kidney disease including diabetic nephropathy (DN). High basal level of autophagy is critical for podocyte health. Recent studies have revealed that hepatocyte growth factor (HGF) can ameliorate podocyte injury and proteinuria. However, little is known about the impact of HGF on podocyte autophagy. In this study, we investigated whether and how HGF affects autophagy in podocytes treated with high glucose (HG) conditions. HGF significantly diminishes apoptosis, oxidative stress and autophagy impairment inflicted by HG in podocytes. These beneficial effects of HGF disappear once HGF receptor is blocked by SU11274, a specific inhibitor of c-Met. Moreover, HGF markedly suppresses HG-stimulated glycogen synthase kinase 3beta (GSK3β) activity. Accordingly, exogenous constitutively-active GSK3β overexpression using an adenoviral vector system (Ad-GSK3β-S9A) abrogates the ability of HGF to ameliorate HG-mediated podocyte injury while neither adenoviral-mediated overexpression of wild-type GSK3β (Ad-GSK3β-WT) nor adenoviral transduction of inactive GSK3β mutant (Ad-GSK3β-K85A) can counteract the protective effects of HGF on HG-treated podocytes. Collectively, these results suggest that HGF prevents HG-induced podocyte injury via an autophagy-promoting mechanism, which involves GSK3β inhibition.