Diabetic retinal neurodegeneration is associated with mitochondrial oxidative stress and is improved by an angiotensin receptor blocker in a model combining hypertension and diabetes.
OBJECTIVE
Diabetic retinopathy displays the features of a neurodegenerative disease. Oxidative stress is involved in the pathogenesis of diabetic retinopathy. This investigation sought to determine whether hypertension exacerbates the oxidative stress, neurodegeneration, and mitochondrial dysfunction that exists in diabetic retinopathy and whether these changes could be minimized by the angiotensin II type 1 (AT(1)) receptor blocker (ARB) losartan.


METHODS
Diabetes was induced in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. The diabetic SHRs were assigned to receive or not receive losartan.


RESULTS
The level of apoptosis in the retina was higher in diabetic WKY rats than in the control group, and higher levels were found in diabetic SHRs. The apoptotic cells expressed neural and glial markers. The retinal glial reaction was more evident in diabetic WKY rats and was markedly accentuated in diabetic SHRs. Superoxide production in retinal tissue increased in diabetic WKY rats, and a greater increase occurred in diabetic SHRs. Glutathione levels decreased only in diabetic SHRs. As a consequence, the levels of nitrotyrosine and 8-hydroxy 2'-deoxyguanosine, markers of oxidative stress, were elevated in diabetic groups, mainly in diabetic SHRs. Mitochondrial integrity was dramatically affected in the diabetic groups. The ARB treatment reestablished all of the above-mentioned parameters.


CONCLUSIONS
These findings suggest that concomitance of hypertension and diabetes exacerbates oxidative stress, neurodegeneration, and mitochondrial dysfunction in the retinal cells. These data provide the first evidence of AT(1)blockage as a neuroprotective treatment of diabetic retinopathy by reestablishing oxidative redox and the mitochondrial function.
Silva
Kamila C
KC
Renal Pathophysiology Laboratory, Investigation on Complications of Diabetes, Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
Rosales
Mariana A B
MA
Biswas
Subrata K
SK
Lopes de Faria
Jose B
JB
Lopes de Faria
Jacqueline M
JM
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004249:DNA Damage; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000503:physiopathology*; D006973:Hypertension / Q000150:complications* / Q000235:genetics; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019808:Losartan / Q000627:therapeutic use*; D008928:Mitochondria / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D057911:Angiotensin Receptor Antagonists; D019808:Losartan