Endothelin receptor antagonist combined with a calcium channel blocker attenuates renal injury in spontaneous hypertensive rats with diabetes.
OBJECTIVE
To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes.


METHODS
Diabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week.


RESULTS
Mean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters.


CONCLUSIONS
Bosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state.
Chen
Jing
J
Division of Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, China.
Gu
Yong
Y
Lin
Fan
F
Yang
Haichun
H
Zhu
Weiyu
W
Ma
Ji
J
Lin
Shanyan
S
D017311:Amlodipine / Q000008:administration & dosage*; D000804:Angiotensin II / Q000032:analysis; D000818:Animals; D000077300:Bosentan; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D024141:Collagen Type IV / Q000032:analysis; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013449:Sulfonamides / Q000008:administration & dosage*; D016212:Transforming Growth Factor beta / Q000032:analysis; D053773:Transforming Growth Factor beta1
D002121:Calcium Channel Blockers; D024141:Collagen Type IV; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D017311:Amlodipine; D000077300:Bosentan