L-Arginine mitigates high glucose-induced podocyte injury via NRF2 pathway activation

L-Arginine, a semi-essential amino acid involved in the ornithine cycle, exhibits therapeutic potential in diabetes through benefits demonstrated in both animal models and human studies. However, the precise mechanisms underlying its effects remain incompletely understood. Podocytes play a crucial role in the pathogenesis of diabetic nephropathy (DN), with podocyte injury contributing significantly to disease progression. In this study, we demonstrated that L-arginine treatment improved podocyte viability, decreased oxidative stress and inflammation markers, and upregulated nuclear factor erythroid 2-related factor 2 (NRF2) expression and its nuclear translocation, along with its downstream antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), in a dose-dependent manner. Importantly, these protective effects were reversed by the NRF2 inhibitor ML385 and Nrf2 RNA interference (RNAi), suggesting that L-arginine's protective mechanism is likely mediated through the NRF2 pathway. These findings emphasize the potential of L-arginine as a therapeutic agent for DN by protecting podocytes from high glucose-induced oxidative stress and injury.