Tinospora cordifolia activates PPARγ pathway and mitigates glomerular and tubular cell injury in diabetic kidney disease

Background: Diabetic Kidney Disease (DKD) is a common complication of diabetes and a leading cause of end-stage renal disease progression. Therefore, therapeutic strategies are desirable to mitigate the progression of disease into more severe consequences.Hypothesis/Purpose:Tinospora cordifolia is a traditionally known antidiabetic plant; however, its effect against DKD remains unexplored. Therefore, in the present study, we assessed the efficacy and mechanism of action of Tinospora cordifolia extract (TC) against DKD.Methods: The molecular interaction of the various phytoconstituents of TC with PPARγ were analyzed in silico. The effect of TC was studied on the viability, cell cycle, and gene expressions (PPARγ, TGFβ, and αSMA) in high glucose treated NRK-52E and SV40 MES13 cells. Further, streptozotocin-induced diabetic rats were treated with TC for eight weeks, and the effects on different biochemical, histological and molecular parameters were studied.Results:In silico analysis revealed the integration of various phytoconstituents of TC with PPARγ. It further increased PPARγ and decreased TGFβ and αSMA expressions in NRK-52E and SV40 MES13 cells. In diabetic rats, TC improved the fasting blood glucose, serum urea, and creatinine levels. It also lowered the urine microalbumin and advanced glycation end products (AGEs) levels. Histopathological studies revealed the preventive effect of TC on degenerative changes, mesangial proliferation and glomerular hypertrophy. Further, it reduced the inflammation and fibrotic changes in the kidney tissue estimated by various markers. The kidney tissue and gene expression analysis revealed the augmented levels of PPARγ after TC treatment.Conclusion: In conclusion, TC exerted the protective effect against DKD by inhibiting inflammation and fibrogenesis through the activation of PPARγ dependent pathways.