Carnosic acid improves diabetic nephropathy by activating Nrf2/ARE and inhibition of NF-κB pathway

Diabetic nephropathy (DN), one of the most serious complications of diabetes, is the leading cause of morbidity and mortality of end-stage renal disease. Our previous research found that carnosic acid (CA) or rosemary extract can effectively improve glucose and lipid metabolism disorder by inhibiting SREBPs.In this study, we aimed to explore the therapeutic effects of CA on the DN.The mice glomerular mesangial cells (mGMCs) were used to evaluate the anti-oxidative and anti-inflammation effects of CA under high glucose (HG) condition. Furthermore, db/db mice and streptozotocin (STZ)-induced diabetic mice were used to investigate the effects of CA against DN in vivo.The results showed that CA activated Nrf2, inhibited NF-κB pathway and regulated related downstream genes in mGMC under HG condition. A 14-week treatment of mice with CA reduced water uptake and urine volume, attenuated diabetes-induced albuminuria, increased urine creatinine, and subsequently improved the glomerular sclerosis and mesangial expansion in db/db mice. Similarly, a 20-week oral administration of CA improved kidney damage in STZ-induced diabetic mice. In addition, CA inhibited the expression of profibrotic factors, such as TGF-β1, fibronectin and E-cadherin. Compared to irbesartan, CA exerted better glucose lowering effect, and in kidney, CA was more potent to reduce fibronectin and E-cadherin expression. In all the animal experiment, CA did not lead to abnormal damages to other tissues.These findings suggest that CA is a safe compound which exerts the protective effects on diabetes-induced kidney complications.