Impact Of Bosentan And Amlodipine On Fibrosis And Microvasculatures In The Kidney Of DOCA-salt Hypertensive Rats

Objectives: This study was performed to investigate the impact of bosentan and amlodipin on fibrosis and microvasculatures in the kidney of DOCA-salt hypertensive rats(DHR).Methods: 24 male Sprague-Dawley rats were uninephrectomized ,given penicillin three days.Then randomly divided into 4 groups.,One group served as control group,drinking tap water.Three other groups were administered DOCA subcutaneously (50mg/kg week)and 1%saline was added to their tap water for drinking. they were treated for 5 weeks with either a long-acting calcium antagonist, amlodipine(20mg/kg day^-1), mixed ET_A-ET_B endothelin receptor antagonist,bosentan(100mg/kg day^-1).or given placebo. At the end of treatment,systolic blood pressure(SBP),24 hour urinary protein excretion rate(24h-UPER),serum blood urea nitrogen(BUN), creatinine(Scr) were measured. Renal histology change was assessed on PAS-stained sections. The protein expressions of renal transforming growth factor(TGF- β 1) and Smad7 were determined by immunohistochemistry at 5^th week.The number of capillary density and proliferating endothelial cells were also counted. Results: DHR exhibited an enhanced 24h-UPER,increased renal histology change ,over-expressions of TGF- β 1 and Smad7 were observed in untreatedDHR compared with control group.All these abnormalities were ameliorated by bosentan, except amlodipine..However, 3UN and Scr remained nomal. The glomerular capillary index(GCI) and peritubular capillary index(PCI) were significantly lower in DHR group than those in control group(P<0.01).The GCI and PCI in antihypertension drug-treated group were significantly higher than those in placebo group,but the GCI and PCI in bosentan were significantly higher than those in amlodipine-treated group(P<0.05).The numbers of glomerular and interstitial proliferating endothelial cells in all antihypertensive drug-treated groups were significantly higher than those in placebo group(P<0.01), but the numbers of proliferating endothelial cells in bosentan group were significantly higher than those in amlodipine-treated group(P<0.05).Conclusion: Bosentan significantly attenuate renal damage, improves angiogenesis and increases capillary density in DHR,suggesting that endothelin-1 may contribute to progression of renal damage via increases the expression of TGF- ￡ 1 and Smad7,direct inhibition of angiogenesis and indirect damage of microvasculature through exacerbation of hypertension.