Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes

Arctigenin (ATG) is a major component of Fructus Arctii, which as a traditional herbal remedy reduced proteinuria in diabetic patients. However, whether ATG specifically provided renoprotection in DKD was not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-?B-mediated inflammatory response and high glucose-induced migration in cultured podocytes via its interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results clearly demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression. Overall design: To elucidate the underlying mechanism of renoprotection conferred by ATG in DKD, we performed the RNA sequencing of isolated glomeruli from the diabetic and control eNOS-/- mice treated with ATG or vehicle. Diabetes was induced in 8-week old mice with intraperitoneal administration of streptozotocin (STZ, Sigma S0130, dissolved in 0.1 M citrate buffer, PH 4.5) at 50mg/kg after 4-6 hours of food deprivation each day for 5 consecutive days. Citrate buffer-injected mice served as nondiabetic controls. 10 weeks after diabetes induction, mice were given ATG (Cayman Chemicals) dissolved in 5% DMSO by oral gavage at a dose of 40mg/kg body weight/day for 8 weeks. 5% DMSO vehicle-treated mice served as controls.