Zingerone attenuates diabetic nephropathy through inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4

Diabetes affects a large proportion of population wide across the world and kidney is a main target organ of diabetic complications. Zingerone is a stable active component derived from dry ginger rhizome. We investigated the effect of zingerone on diabetic nephropathy and explored the possible mechanisms. We showed that zingerone decreased the levels of serum insulin, C-peptide and glycosylated hemoglobin A1c. The levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR) were reduced by zingerone. Moreover, zingerone attenuated the pathological injuries of kidneys, reduced the surface area of Bowman's capsule, Bowman's space, glomerular tuft, and decreased the expression of collagen IV and fibronectin in kidneys in db/db mice. The high levels of triglyceride and cholesterol, and high expression of TNFɑ and IL-6 were decreased by zingerone. Furthermore, zingerone decreased the level of MDA and increased the content of glutathione (GSH). NADPH oxidase 4 (NOX4) expression was significantly increased in kidneys of db/db mice and in HK-2 cells after exposure to high glucose. Zingerone significantly decreased the expression of NOX4 in vivo and in vitro. Upregualtion of NOX4 significantly inhibited zingerone-induced protective effects against the cytotoxicity of high glucose. Downregulation of NOX4 was responsible for zingerone-exhibited pharmacological activities and reduction of diabetic nephropathy. Overall, zingerone is a promising therapeutic treatment to attenuate diabetic nephropathy.