Salvianolic acid A ameliorates AGEs-induced glomerular endothelial dysfunction and protects against diabetic nephropathy

Bi-yu HOU,Yue-rong ZHAO,2,Gui-fen QIANG,Xi CHEN,Xiu-ying YANG,Li ZHANG,Guan-hua DU

(1.Beijing Key Laboratory of Drug Target Identification and Drug Screening,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;2.School of Traditional Chinese Medicine,Guangdong Pharmaceutical University,Guangzhou 510006,China)

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Salvianolic acid A ameliorates AGEs-induced glomerular endothelial dysfunction and protects against diabetic nephropathy

Bi-yu HOU1,Yue-rong ZHAO1,2,Gui-fen QIANG1,Xi CHEN1,Xiu-ying YANG1,Li ZHANG1,Guan-hua DU1

(1.Beijing Key Laboratory of Drug Target Identification and Drug Screening,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;2.School of Traditional Chinese Medicine,Guangdong Pharmaceutical University,Guangzhou 510006,China)

OBJECTIVEDiabetic 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.METHODSPrimary 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.RESULTSSalA 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-1markedly reduced endothelium loss(P＜0.01)and glomerular hyperfiltration(P＜0.05)in diabetic kidney.Subsequently，SalA 1 mg·kg-1suppressed 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.CONCLUSIONSalA 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.

salvianolic acid A;diabetic nephropathy;glomerular hyperfiltration

The project supported by National Nature Science Foundation of China(81770847)；CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-3-007,2016-I2M-1-010);and National Key Research and Development Plan(2016YFC1000905)

Li ZHANG,E-mail:zhangli@imm.ac.cn;Guan-hua DU,E-mail:dugh@imm.ac.cn Tel:(010)63165184,Fax:(010)63165184