Diabetic nephropathy (DN) is one of the most serious diabetic complications with the most prominent mortality. Though the capacity of hesperetin to preserve renal function has been reported, studies on its effect on major biochemical pathways involved in the protection of renal function are still needed. This study aimed to confirm the effect of hesperetin on blood glucose and evaluate its effect on pathways responsible for efficient kidney function. The effect of orally administered hesperetin on oxidative damage induced by streptozotocin (STZ)-in rats was investigated. Forty-eight Wistar rats were randomly assigned and given an intraperitoneal injection of STZ (60 mg/kg) to induce diabetes with some un-induced (control). Experimental rats were divided into six groups; control, diabetic control, diabetic rats treated with hesperetin (50, 20, and 40 mg/kg), and diabetic rats treated with metformin (100 mg/kg) daily for three weeks. The expression of HO-1, biliverdin reductase (BLVRD), ICAM-1, NF-KB, and VCAM-1 genes were assessed in renal tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). The lipid profile and level of liver function enzymes were also assessed. A computational approach was conducted to determine the molecular interaction of metformin and hesperetin with HO-1 and BLVRD. Significant up-regulation of HO-1, BLVRD, and Nrf2 together with down-regulation of NF-kB, I-CAM, and V-CAM was observed in diabetic rats treated with hesperetin and metformin when compared to diabetic control rats (p<0.05). Treatment of diabetic rats with hesperetin restored lipid profile and liver function markers to normalcy. Hesperetin exhibited more favorable interaction with BLVRD and HO-1 (-8.0 kcal/mol for HO-1 and -8.2 kcal/mol, respectively) compared with metformin. Hesperetin exhibits renal-protective effects and reduces oxidative stress and inflammation in the STZ diabetic rat model, which may be mediated by up-regulation of the Nrf2/HO-1/BLVRD pathway and down-regulation of NF-κB and its downstream genes.
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