Polygala Fallax Hemsl Ameliorates Renal Dysfunction and Podocyte Mitochondrial Oxidative Damage in Diabetic Rats by Activating the AMPK/SIRT1/PGC-1α Signaling

Abstract

Backgrounds: Diabetic nephropathy (DN) is a microvascular disease affecting the glomeruli and renal tubules, resulting from diabetes mellitus. Our present experiment was designed to assess the potential therapeutic of Polygala fallax Hemsl (PFH) on DN in diabetic rats. Methods: As a model of DN, Sprague-Dawley (SD) rats were fed a high-sugar, high-fat diet with streptozotocin (STZ) intraperitoneally injected. The rats that exhibited successful modeling were randomly allocated into different groups, including the model group, as well as PFH low (2 g/kg), medium (4 g/kg), and high (8 g/kg) dose groups. Additionally, there was a positive drug group treated with Losartan Possaium (LP) at a dosage of 16 mg/kg. The general condition of rats was observed, and biochemical tests were conducted. Histopathological changes in renal tissue were assessed using staining techniques such as Hematoxylin-eosin (H&E), periodic acid-Schiff (PAS), and Masson staining. Immunofluorescence (IF), immunohistochemistry (IHC), and Western blot analyses were utilized to assess protein expression levels in renal tissue. Results: Intragastric administration of PFH for 4 weeks in diabetic rats dose-dependently decreased renal weight/body weight (p < 0.05 or p < 0.01), insulin resistance (p < 0.05 or p < 0.01), total cholesterol (TC; p > 0.05 or p < 0.01), triglyceride (TG; p < 0.05 or p < 0.01), serum albumin (ALB; p < 0.01), creatinine (CREA; p < 0.05 or p < 0.01), carbamide (UREA; p < 0.01), alanine aminotransferase (ALT; p < 0.01), aspartate aminotransferase (AST; p < 0.05 or p < 0.01) levels. PFH significantly inhibited podocyte damage, basement membrane thickening, renal tubular epithelial cell swelling, and inflammatory cell infiltration. Moreover, PFH dose-dependently promoted mitochondrial membrane potential (MMP; p < 0.05 or p < 0.01) and inhibited reactive oxygen species (ROS; p < 0.01) generation, podocyte apoptosis (p < 0.01), mitochondrial fragmentation, and dysfunction in vivo. Besides, the high-dose PFH treatment group had a similar improvement effect on podocyte mitochondrial damage andapoptosis as the positive drug control group. Mechanistically, PFH could stabilize mitochondrial morphology in podocytes via activation of AMP-activated protein kinase (AMPK)/silent information regulator sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α signaling. Conclusion: Thus, PFH mitigated mitochondrial dysfunction and oxidative damage in renal podocytes of DN rats, thereby safeguarding renal function. This protective mechanism is believed to involve the mobilisation of the AMPK/SIRT1/PGC-1α axis.