Diabetic Retinal Neurodegeneration Is Associated With Mitochondrial Oxidative Stress and Is Improved by an Angiotensin Receptor Blocker in a Model Combining Hypertension and Diabetes

Abstract

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.RESEARCH DESIGN AND 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 2Ј-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. Diabetes

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

“…ACE inhibition and ARB improve aspects of neuronal and glial damage in both situations [42], such as ameliorating losses in the electroretinogram [25,38,43] and neuronal and glial cell degeneration [44][45][46]. Our identification of renin in retinal Müller cells [2] and ganglion cells [3] is suggestive that aliskiren may influence these cell populations.…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…155 Consumption of dark chocolate is associated with blood pressure reduction associated with a reduction in oxidative stress and increase in nitric oxide bioavailability, 156 both abnormalities that have been involved in the pathogenesis of diabetic nephropathy and retinopathy. 67,[85][86][87][88][93][94][95][97][98][99]156 Finally, in experimental diabetes, the use of green tea was associated with an improvement in diabetic nephropathy and retinopathy and associated with a reduction in oxidative stress. 91, 157 The usefulness of these dietary approaches in diabetic patients with hypertension and nephropathy or retinopathy that are on standard treatment deserves to be tested in larger clinical trials.…”

“…Experimental and clinical studies have demonstrated that these maneuvers are also able to reduce superoxide generation and/or increase anti-oxidant defenses. 98,99,148,149 In this review, we have provided evidence that local generation of oxidative stress and inflammation can be a common mechanism of renal and retinal lesion in the presence of diabetes and hypertension. Although efficient, blood glucose control, normalization of arterial pressure and drugs that interfere in RAAS are currently unable to completely arrest diabetic renal and retinal diseases.…”

“…98 An AT1 receptor blockade with losartan also reduces retinal damage by decreasing inflammation and oxidative stress by means of a reduction in retinal inducible nitric oxide. 99 These findings indicate that the blockage of RAS exerts a variety of effects, including antioxidant, anti-apoptotic and anti-inflammatory properties. [98][99][100] Collectively, the above findings suggest that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension (Figure 1).…”

“…84 In the retina, a number of studies have shown that there is an increase in oxidative markers after the induction of DM, 67,[93][94][95] but the concomitance of diabetes and hypertension evoked earlier oxidative retinal damage characterized by an increase in nitrotyrosine and 8-OHdG in retinal tissue from short-term STZ-induced DM in SHRs. [96][97][98][99] These oxidative markers were the consequence of an increase in superoxide production and depletion of the gluthationereduced antioxidant system in the retinal tissue. [96][97][98] Interestingly, the administration of a superoxide dismutase mimetic tempol to diabetic SHRs re-established the redox status and improved early molecular markers of DR. 97 In these models, with long-term diabetes (12 weeks of duration), we have demonstrated that hypertension could account for exacerbation of retinopathy in diabetic SHRs.…”