Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine

1 Physical-Chemistry Department, School of Pharmacy and Biochemistry, University of Buenos Aires; 2 Laboratory of Experimental Medicine, Hospital Aleman, Buenos Aires, Argentina; 3 Department of Physiology, Ponce School of Medicine, Ponce, Puerto Rico; and 4 Laboratory of Experimental Nephrology, Institute of Cardiovascular Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina Submitted 24 August 2005 ; accepted in final form 5 January 2006 Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1 ) kidney impairment is related to mitochondrial dysfunction; and 2 ) ANG II blockade, compared with Ca 2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg·kg –1 ·day –1 , SHR+Los), amlodipine (3 mg·kg –1 ·day –1 , SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H 2 O 2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial -smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT 1 -receptor antagonists. kidney disease; nitric oxide; mitochondria; oxidative stress; hypertension Address for reprint requests and other correspondence: F. Inserra, Institute for Cardiovascular Research (ININCA), School