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

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.