Salvianolic acid A ameliorates AGEs-induced glomerular endothelial dysfunction and protects against diabetic nephropathy / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE Diabetic nephropathy (DN) has been one of the most common complications of diabetes and the leading cause of end-stage renal disease. Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities. Salvi?anolic acid A (SalA) has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy. The present study was designed to investigate the effects of SalAon glomerular endothelial dysfunctionand diabetic nephropathy. METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products (AGEs). AGEs-induced changes of RhoA/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunoflu?orescence. The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin (35 mg·kg- 1, ip). Renal function and architectonic changes were evaluated by biochemical assay and PAS staining. RESULTS SalA 3μMameliorated AGEs- induced glomerular endothelial permeability (P<0.05) and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-RhoA/ROCK pathway. SalA 1 mg · kg- 1 markedly reduced endothelium loss (P<0.01) and glomerular hyperfiltration (P<0.05) in diabetic kidney. Subsequently,SalA 1 mg·kg-1 suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen (BUN), serum creatinine (Scr) and serum n-acetyl-β-d-glucosaminidase (NAG). AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg-1. CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability, and effec?tively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway. Thus, SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.