GSTP1-Mediated Inhibition of Rac1-Mineralocorticoid Receptor Signaling Underlies the Renoprotective Effect of Huangqi Tujian Decoction in Diabetic Nephropathy.

Abstract

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, and current therapies often fail to adequately address oxidative stress-induced podocyte injury. Huangqi Tujian Decoction (HTD), a traditional Chinese herbal formula, has shown promise in the clinical management of DN, yet its molecular mechanisms remain incompletely understood. This study aimed to elucidate the protective role of HTD and its interplay with glutathione S-transferase P1 (GSTP1) and the Rac1-mineralocorticoid receptor (MR) signaling pathway. Integrated bioinformatic analysis of human DN transcriptomes identified GSTP1 as a central hub gene. In vivo studies using db/db mice and streptozotocin-induced GSTP1-knockout models revealed that HTD significantly improved renal function; reduced albuminuria, serum creatinine, and blood urea nitrogen levels; and restored podocyte integrity markers (ZO-1 and Nephrin). HTD treatment also suppressed Rac1-MR activation and downregulated NADPH oxidase subunits, thereby alleviating oxidative stress and apoptosis. Importantly, GSTP1 deficiency completely abolished these protective effects. Coimmunoprecipitation assays demonstrated direct binding between GSTP1 and both Rac1 and MR, suggesting that GSTP1 disrupts the pathogenic Rac1-MR complex. In summary, HTD ameliorates DN by normalizing GSTP1 expression toward physiological levels, thereby disrupting the pathogenic Rac1-MR complex and attenuating oxidative damage and podocyte injury. These findings reveal a novel molecular pathway for HTD and highlight GSTP1 as a promising therapeutic target and potential biomarker for DN.