title: Co-inhibition of Angiotensin II Receptor and Endothelin-1 Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice.
abstract: OBJECTIVE
  Both endothelin-1 (ET-1) and the renin-angiotensin system (RAS) may play important roles in renal fibrosis in the obstructed kidney. However, there have been few clear demonstrations of a relationship between their activation and additive or synergistic roles in renal fibrosis. We investigated the protective roles and relationship between renal RAS and ET-1 in unilateral ureteral obstruction (UUO) mice.
  
  
  METHODS
  8-week-old male C57BL/6 mice were divided into seven groups: sham, bosentan+sham, valsartan+sham, vehicle+UUO, bosentan+UUO, valsartan+UUO, and valsartan+bosentan+UUO. Valsartan and bosentan were administered orally using an NG tube (valsartan 10 mg/kg/day, bosentan 100 mg/kg/day for 8 days, after which the molecular and structural kidney parameters were evaluated. Bosentan treatment elevated plasma renin activity, renal renin, and AT1R expression in UUO mice.
  
  
  RESULTS
  Although valsartan decreased plasma ET-1 in these mice, it did not affect ET(A) or ET(B) in their kidneys. Co-treatment with valsartan and bosentan decreased ET-1 in these mice compared to the single treatments. Bosentan, but not valsartan, elevated eNOS expression in their kidneys. Co-treatment with valsartan and bosentan reduced TGF-β, α-SMA, and collagen IV expression, and the Masson's trichrome stained area in their kidneys.
  
  
  CONCLUSIONS
  Bosentan and valsartan acted complementarily, and co-treatment with both drugs had an additive protective effect against renal fibrosis.
authors.affiliation: Department of Nephrology, Daejeon St. Mary Hospital, Daejeon, Korea.
authors.forename: Yoon-Kyung
authors.initials: YK
authors.lastname: Chang
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Choi
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Jeong
authors.forename: Ki-Ryang
authors.initials: KR
authors.lastname: Na
authors.forename: Kang Wook
authors.initials: KW
authors.lastname: Lee
authors.forename: Dae Eun
authors.initials: DE
authors.lastname: Choi
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000517:prevention & control; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D000077300:Bosentan; D004357:Drug Synergism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011945:Receptors, Angiotensin / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014517:Ureteral Obstruction / Q000188:drug therapy*; D000068756:Valsartan / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D011945:Receptors, Angiotensin; D013449:Sulfonamides; D000068756:Valsartan; D000077300:Bosentan