Journal
JOURNAL OF HYPERTENSION
Volume 26, Issue 10, Pages 2022-2029Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0b013e328309f00a
Keywords
angiotensin-converting enzyme-inhibition; endothelin-1; kidney fibrosis; L-type calcium channels
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Funding
- FORICA (The FOundation for advanced Research In Hypertension and CArdiovascular diseases)
- The University of Padua
- Societa Italiana dell'Ipertensione Arteriosa
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Objective Fibrosis is a hallmark of renal damage in several diseases, including arterial hypertension. We, therefore, investigated the role of angiotensin II, endothelin-1 and of L-type calcium channels in the development of the glomerular, vascular, and tubulointerstitial fibrosis in a model of severe angiotensin II-dependent hypertension. Methods Five-week-old Ren-2 transgenic rats (TGRen2) received for 4 weeks a placebo, bosentan (100 mg/kg body weight), irbesartan (50 mg/kg body weight), the ETA-selective endothelin receptor antagonist BMS-182874 (BMS; 52 mg/kg body weight), the combination of irbesartan (50 mg/kg body weight) plus BMS (52 mg/kg body weight), and nifedipine (30 mg/kg body weight). Results Glomerular volume, tubulointerstitial fibrosis, glomerular, and perivascular fibrosis were accurately quantified by histomorphometry in four-to-six sections per kidney. Glomerular fibrosis was lowered by BMS (P< 0.001), whereas tubulointerstitial fibrosis was blunted by bosentan (P< 0.001) and irbesartan (P< 0.005). Perivascular fibrosis was reduced by nifedipine and BMS. As only irbesartan and irbesartan plus BMS decreased blood pressure (P< 0.001 vs. placebo), these effects on fibrosis were independent of blood pressure. Conclusion Angiotensin II and L-type calcium channels modulate fibrosis selectively in the tubulointerstitial and in the perivascular compartments, respectively. The prevention of fibrosis with ET-1 receptor antagonism in all three compartments supports a major role of ET-1 in the development of renal fibrosis.
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