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Renal mitochondrial impairment is attenuated by AT₁ blockade in experimental Type I diabetes

¹Physical-Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina; ²Department of Physiology, Ponce School of Medicine, Ponce, Puerto Rico; ³Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina; ⁴Department of Nutrition, University of California, Davis, California; and ⁵Laboratory of Experimental Nephrology, Institute of Cardiovascular Research, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina

Submitted 9 August 2007 ; accepted in final form 9 November 2007

To investigate whether ANG II type 1 (AT₁) receptor blockade could protect kidney mitochondria in streptozotocin-induced Type 1 diabetes, we treated 8-wk-old male Sprague-Dawley rats with a single streptozotocin injection (65 mg/kg ip; STZ group), streptozotocin and drinking water containing either losartan (30 mg·kg^–1·day^–1; STZ+Los group) or amlodipine (3 mg·kg^–1·day^–1; STZ+Amlo group), or saline (intraperitoneally) and pure water (control group). Four-month-long losartan or amlodipine treatments started 30 days before streptozotocin injection to improve the antioxidant defenses. The number of renal lesions, plasma glucose and lipid levels, and proteinuria were higher and creatinine clearance was lower in STZ and STZ+Amlo compared with STZ+Los and control groups. Glycemia was higher in STZ+Los compared with control. Blood pressure, basal mitochondrial membrane potential and mitochondrial pyruvate content, and renal oxidized glutathione levels were higher and NADH/cytochrome c oxidoreductase activity was lower in STZ compared with the other groups. In STZ and STZ+Amlo groups, mitochondrial H₂O₂ production rate was higher and uncoupling protein-2 content, cytochrome c oxidase activity, and renal glutathione level were lower than in STZ+Los and control groups. Mitochondrial nitric oxide synthase activity was higher in STZ+Amlo compared with the other groups. Mitochondrial pyruvate content and H₂O₂ production rate negatively contributed to electron transfer capacity and positively contributed to renal lesions. Uncoupling protein-2 content negatively contributed to mitochondrial H₂O₂ production rate and renal lesions. Renal glutathione reduction potential positively contributed to mitochondria electron transfer capacity. In conclusion, AT₁ blockade protects kidney mitochondria and kidney structure in streptozotocin-induced diabetes independently of blood pressure and glycemia.

renin-angiotensin system; reactive oxygen species; angiotensin AT₁ receptor blockers

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