Nephroprotective effects of honokiol in a high-fat diet-streptozotocin rat model of diabetic nephropathy

Diabetic nephropathy (DN) is the foremost basis of end-stage kidney failure implicating endoplasmic reticulum (ER) stress and dysregulation of Rho kinase/Rock pathway. Magnolia plants are used in traditional medicine systems in Southeast Asia owing to bioactive phytoconstituents. Earlier, honokiol (Hon) exhibited therapeutic potential in experimental models of metabolic, renal, and brain disorders. In the present study, we evaluated potential of Hon against DN and possible molecular mechanisms. In the existing experiments, high-fat diet (HFD) (17 weeks) and streptozotocin (STZ) (40 mg/kg once) induced DN rats were orally treated with Hon (25, 50, 100 mg/kg) or metformin (150 mg/kg) for 8 weeks. Hon attenuated albuminuria, blood biomarkers (e.g., urea nitrogen, glucose, C-reactive protein, and creatinine) and ameliorated lipid profile, electrolytes levels (Na+/K+), and creatinine clearance against DN. Hon significantly decreased renal oxidative stress and inflammatory biomarkers against DN. Histomorphometry and microscopic analysis revealed nephroprotective effects of Hon marked by a decrease in leukocyte infiltration, renal tissue damage, and urine sediments. RT-qPCR showed that Hon treatment attenuated mRNA expression of transforming growth factor-β1 (TGF-β1), endothelin-1 (ET-1), ER stress markers (GRP78, CHOP, ATF4, and TRB3), and Rock 1/2 in DN rats. Data from ELISA supported a decrease in levels of TGF-β1, ET-1, ER stress markers, and Rock1/2 by Hon. Hon attenuated hyperglycemia, redox imbalance, and inflammation and improved renal functions in rats. Hon alleviates DN pathogenesis possibly by attenuating ER stress and Rock pathway.