TDAG51-Deficiency Podocytes are Protected from High-Glucose-Induced Damage Through Nrf2 Activation via the AKT-GSK-3β Pathway.

Abstract

T cell death-associated gene 51 (TDAG51) has been implicated in the development of various pathological conditions. However, whether TDAG51 plays a role in diabetic renal disease remains unknown. The current work investigated the possible function of TDAG51 in diabetic renal disease using high-glucose (HG)-stimulated podocytes in vitro. The elevation of TDAG51 was observed in podocytes in response to HG exposure and the glomeruli of diabetic mice. The siRNAs targeting TDAG51 were applied to deplete TDAG51 in HG-stimulated podocytes. Crucially, TDAG51 deficiency was sufficient to decrease the apoptosis, oxidative stress, and inflammation caused by HG. Mechanically, the inhibition of TDAG51 was capable of enhancing the activation of nuclear factor E2-related factor 2 (Nrf2) associated with the upregulation of AKT-glycogen synthase kinase-3β (GSK-3β) pathway. The reduction of AKT abolished the activation of Nrf2 elicited by TDAG51 deficiency. Additionally, the reduction of Nrf2 diminished the anti-HG injury effect elicited by TDAG51 deficiency. Overall, these data demonstrate that TDAG51 deficiency defends against HG-induced podocyte damage through Nrf2 activation by regulating AKT-GSK-3β pathway. This study suggests that TDAG1 may have a potential role in diabetic renal disease by affecting HG-induced podocyte damage.