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RENAL HEMODYNAMICS AND CARDIORENAL INTEGRATION

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

¹Physical-Chemistry Department, School of Pharmacy and Biochemistry, University of Buenos Aires; ²Laboratory of Experimental Medicine, Hospital Aleman, Buenos Aires, Argentina; ³Department of Physiology, Ponce School of Medicine, Ponce, Puerto Rico; and ⁴Laboratory 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 Ca²⁺ 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 H₂O₂ 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 AT₁-receptor antagonists.

kidney disease; nitric oxide; mitochondria; oxidative stress; hypertension

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