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Diabetic retinal neurodegeneration is associated with mitochondrial oxidative stress and is improved by an angiotensin receptor blocker in a model combining hypertension and diabetes.

Silva KC, Rosales MA, Biswas SK, Lopes de Faria JB, Lopes de Faria JM - Diabetes (2009)

Bottom Line: Glutathione levels decreased only in diabetic SHRs.The ARB treatment reestablished all of the above-mentioned parameters.These findings suggest that concomitance of hypertension and diabetes exacerbates oxidative stress, neurodegeneration, and mitochondrial dysfunction in the retinal cells.

View Article: PubMed Central - PubMed

Affiliation: Renal Pathophysiology Laboratory, Investigation on Complications of Diabetes, Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.

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 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.

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Evaluation of glial cell reactivity by GFAP immunofluorescence in retinas of control and diabetic WKY and spontaneously hypertensive rats. The presence of diabetes or hypertension alone induced a clear increase in GFAP immunoreactivity throughout the retina. The concomitance of both provoked a further increase in glial reactivity, and the losartan treatment abolished this effect. Bars = means ± SD of percentage of fluorescence per millimeter squared of retina. Scale bars = 50 μm. The graph shows 1.3 ± 0.3 vs. 5.3 ± 0.5% of fluorescence/mm2 of retina for control WKY vs. diabetic WKY rats, *P < 0.0001; 5.3 ± 0.5 vs. 4.9 ± 0.08% of fluorescence/mm2 of retina for diabetic WKY rats vs. control SHRs, P = 0.4; 4.9 ± 0.08 vs. 10.8 ± 0.5% of fluorescence/mm2 of retina for control SHRs vs. diabetic SHRs, †P < 0.0001; 10.8 ± 0.5 vs. 4.7 ± 0.5% of fluorescence/mm2 of retina for diabetic SHRs vs. diabetic losartan (Los)-treated SHRs, †P < 0.0001. CT, control; DM, diabetic; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer; OPL, outer plexiform layer. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 3: Evaluation of glial cell reactivity by GFAP immunofluorescence in retinas of control and diabetic WKY and spontaneously hypertensive rats. The presence of diabetes or hypertension alone induced a clear increase in GFAP immunoreactivity throughout the retina. The concomitance of both provoked a further increase in glial reactivity, and the losartan treatment abolished this effect. Bars = means ± SD of percentage of fluorescence per millimeter squared of retina. Scale bars = 50 μm. The graph shows 1.3 ± 0.3 vs. 5.3 ± 0.5% of fluorescence/mm2 of retina for control WKY vs. diabetic WKY rats, *P < 0.0001; 5.3 ± 0.5 vs. 4.9 ± 0.08% of fluorescence/mm2 of retina for diabetic WKY rats vs. control SHRs, P = 0.4; 4.9 ± 0.08 vs. 10.8 ± 0.5% of fluorescence/mm2 of retina for control SHRs vs. diabetic SHRs, †P < 0.0001; 10.8 ± 0.5 vs. 4.7 ± 0.5% of fluorescence/mm2 of retina for diabetic SHRs vs. diabetic losartan (Los)-treated SHRs, †P < 0.0001. CT, control; DM, diabetic; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer; OPL, outer plexiform layer. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Retinal glial reaction, demonstrated by a local increase in GFAP expression, is an early marker in the pathogenesis of diabetic retinopathy (26). In the retina of control WKY rats, GFAP positivity is minimally apparent. In contrast, after diabetes induction there was an accentuated increase in glial reactivity (P < 0.0001). Similarly observed in diabetic WKY rats, there was a moderate glial reaction throughout the retina in control SHRs (P = 0.4), and the concomitance of both diabetes and hypertension extensively exacerbated the GFAP staining in retinal tissue (P < 0.0001). The treatment prevented the retinal glial reaction seen in diabetic SHRs, which remained similar to control levels (P < 0.0001) (Fig. 3).


Diabetic retinal neurodegeneration is associated with mitochondrial oxidative stress and is improved by an angiotensin receptor blocker in a model combining hypertension and diabetes.

Silva KC, Rosales MA, Biswas SK, Lopes de Faria JB, Lopes de Faria JM - Diabetes (2009)

Evaluation of glial cell reactivity by GFAP immunofluorescence in retinas of control and diabetic WKY and spontaneously hypertensive rats. The presence of diabetes or hypertension alone induced a clear increase in GFAP immunoreactivity throughout the retina. The concomitance of both provoked a further increase in glial reactivity, and the losartan treatment abolished this effect. Bars = means ± SD of percentage of fluorescence per millimeter squared of retina. Scale bars = 50 μm. The graph shows 1.3 ± 0.3 vs. 5.3 ± 0.5% of fluorescence/mm2 of retina for control WKY vs. diabetic WKY rats, *P < 0.0001; 5.3 ± 0.5 vs. 4.9 ± 0.08% of fluorescence/mm2 of retina for diabetic WKY rats vs. control SHRs, P = 0.4; 4.9 ± 0.08 vs. 10.8 ± 0.5% of fluorescence/mm2 of retina for control SHRs vs. diabetic SHRs, †P < 0.0001; 10.8 ± 0.5 vs. 4.7 ± 0.5% of fluorescence/mm2 of retina for diabetic SHRs vs. diabetic losartan (Los)-treated SHRs, †P < 0.0001. CT, control; DM, diabetic; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer; OPL, outer plexiform layer. (A high-quality digital representation of this figure is available in the online issue.)
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Related In: Results  -  Collection

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Figure 3: Evaluation of glial cell reactivity by GFAP immunofluorescence in retinas of control and diabetic WKY and spontaneously hypertensive rats. The presence of diabetes or hypertension alone induced a clear increase in GFAP immunoreactivity throughout the retina. The concomitance of both provoked a further increase in glial reactivity, and the losartan treatment abolished this effect. Bars = means ± SD of percentage of fluorescence per millimeter squared of retina. Scale bars = 50 μm. The graph shows 1.3 ± 0.3 vs. 5.3 ± 0.5% of fluorescence/mm2 of retina for control WKY vs. diabetic WKY rats, *P < 0.0001; 5.3 ± 0.5 vs. 4.9 ± 0.08% of fluorescence/mm2 of retina for diabetic WKY rats vs. control SHRs, P = 0.4; 4.9 ± 0.08 vs. 10.8 ± 0.5% of fluorescence/mm2 of retina for control SHRs vs. diabetic SHRs, †P < 0.0001; 10.8 ± 0.5 vs. 4.7 ± 0.5% of fluorescence/mm2 of retina for diabetic SHRs vs. diabetic losartan (Los)-treated SHRs, †P < 0.0001. CT, control; DM, diabetic; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer; OPL, outer plexiform layer. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Retinal glial reaction, demonstrated by a local increase in GFAP expression, is an early marker in the pathogenesis of diabetic retinopathy (26). In the retina of control WKY rats, GFAP positivity is minimally apparent. In contrast, after diabetes induction there was an accentuated increase in glial reactivity (P < 0.0001). Similarly observed in diabetic WKY rats, there was a moderate glial reaction throughout the retina in control SHRs (P = 0.4), and the concomitance of both diabetes and hypertension extensively exacerbated the GFAP staining in retinal tissue (P < 0.0001). The treatment prevented the retinal glial reaction seen in diabetic SHRs, which remained similar to control levels (P < 0.0001) (Fig. 3).

Bottom Line: Glutathione levels decreased only in diabetic SHRs.The ARB treatment reestablished all of the above-mentioned parameters.These findings suggest that concomitance of hypertension and diabetes exacerbates oxidative stress, neurodegeneration, and mitochondrial dysfunction in the retinal cells.

View Article: PubMed Central - PubMed

Affiliation: Renal Pathophysiology Laboratory, Investigation on Complications of Diabetes, Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.

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 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.

Show MeSH
Related in: MedlinePlus