Role of angiotensin II, endothelin-1 and L-type calcium channel in the development of glomerular, tubulointerstitial and perivascular fibrosis.
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.


CONCLUSIONS
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.
Seccia
Teresa M
TM
DMCS-Internal Medicine 4, University of Padova, Padova, Italy.
Maniero
Carmen
C
Belloni
Anna S
AS
Guidolin
Diego
D
Pothen
Poulose
P
Pessina
Achille C
AC
Rossi
Gian Paolo
GP
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D020746:Calcium Channels, L-Type / Q000502:physiology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000502:physiology*; D005355:Fibrosis; D007676:Kidney Failure, Chronic / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051381:Rats
D020746:Calcium Channels, L-Type; D019332:Endothelin-1; D000804:Angiotensin II