Perillaldehyde Attenuates Diabetic Nephropathy through Modulation of the Nrf2/Keap1 and NF‐κB Signalling Pathways

ABSTRACT

Diabetic nephropathy (DN) is a one of the common microvascular complication of diabetes that involves oxidative stress, inflammation, activation and overexpression of Nuclear factor kappa B (NF‐κB), and chronic renal dysfunction. In this study, we evaluated the renoprotective role of perillaldehyde (PA) in protecting kidneys from diabetic nephropathy using in vitro and in vivo models of Streptozotocin‐induced diabetic nephropathy. PA pre‐treatment of NRK‐52E cells under high‐glucose conditions resulted in a significant reduction of reactive oxygen species formation, up‐regulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), suppression of Kelch‐like ECH‐associated protein 1 (Keap1), and elevation of antioxidant enzyme biomarkers, such as heme oxygenase 1, superoxide dismutase 1, and NAD(P)H dehydrogenase quinone 1. PA also inhibited the overexpression of NF‐κB, inducible nitric oxide synthase, and poly (ADP‐ribose) polymerase in high‐glucose exposed NRK‐52E cells. Administration of PA (35 and 70 mg/kg) to streptozotocin‐induced diabetic rats showed beneficial effects on renal function parameters such as creatinine and blood urea nitrogen. PA treatment attenuated glomerular and tubular structural damage, as evidenced by H&E and PAS staining. At molecular level, PA was found to maintain the redox balance in the kidneys by stimulating the Nrf2/Keap1/HO‐1 signalling pathway and inhibiting the NF‐κB‐dependent inflammatory response. Moreover, PA lowered lipid peroxidation and enhanced antioxidant status via reduction in MDA and elevation in GSH. The above results indicated that PA showed considerable reno‐protective actions through coordinated regulation of both oxidative stress and inflammation pathways in experimental models of diabetic nephropathy