The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats.
Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.
Crary
G S
GS
Department of Pathology, Hennepin County Medical Center, Minneapolis, MN, USA.
Swan
S K
SK
O'Donnell
M P
MP
Kasiske
B L
BL
Katz
S A
SA
Keane
W F
WF
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D019808:Losartan; D008297:Male; D009765:Obesity / Q000473:pathology* / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan