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Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function.

Miller AG, Tan G, Binger KJ, Pickering RJ, Thomas MC, Nagaraj RH, Cooper ME, Wilkinson-Berka JL - Diabetes (2010)

Bottom Line: In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO(•)), the latter being a known negative regulator of GLO-I in BRP.In BREC and BRP, candesartan restored GLO-I and reduced NO(•).Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO-I.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia. antonia.miller@monash.edu

ABSTRACT

Objective: Advanced glycation end products (AGEs) and the renin-angiotensin system (RAS) are both implicated in the development of diabetic retinopathy. How these pathways interact to promote retinal vasculopathy is not fully understood. Glyoxalase-I (GLO-I) is an enzyme critical for the detoxification of AGEs and retinal vascular cell survival. We hypothesized that, in retina, angiotensin II (Ang II) downregulates GLO-I, which leads to an increase in methylglyoxal-AGE formation. The angiotensin type 1 receptor blocker, candesartan, rectifies this imbalance and protects against retinal vasculopathy.

Research design and methods: Cultured bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRP) were incubated with Ang II (100 nmol/l) or Ang II+candesartan (1 μmol/l). Transgenic Ren-2 rats that overexpress the RAS were randomized to be nondiabetic, diabetic, or diabetic+candesartan (5 mg/kg/day) and studied over 20 weeks. Comparisons were made with diabetic Sprague-Dawley rats.

Results: In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO(•)), the latter being a known negative regulator of GLO-I in BRP. In BREC and BRP, candesartan restored GLO-I and reduced NO(•). Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO-I. In diabetic Ren-2 rats, candesartan reduced retinal acellular capillaries, inflammation, and inducible nitric oxide synthase and NO(•), and restored GLO-I.

Conclusions: We have identified a novel mechanism by which candesartan improves diabetic retinopathy through the restoration of GLO-I.

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Related in: MedlinePlus

Proposed mechanism by which Ang II downregulates GLO-I in retinal vascular cells, leading to the generation of AGEs and vascular injury. The AT1-RB, Cand, is able to prevent diabetic retinal vascular injury by reducing nitric oxide and restoring GLO-I levels.
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Figure 8: Proposed mechanism by which Ang II downregulates GLO-I in retinal vascular cells, leading to the generation of AGEs and vascular injury. The AT1-RB, Cand, is able to prevent diabetic retinal vascular injury by reducing nitric oxide and restoring GLO-I levels.

Mentions: The present study provides novel evidence that GLO-I, an enzyme critical for retinal vascular cell survival (12), is downregulated by Ang II in the retina. Our findings are supported by evidence that the AT1-RB, candesartan, improves acellular capillary formation and inflammation in diabetic retinopathy with a concomitant restoration of retinal GLO-I expression and a reduction of MGO-AGEs and, in particular, the specific MGO-AGE argpyrimidine. These findings broaden the known actions of Ang II in the AGE pathway to include not only extracellular AGE-related events such as RAGE-mediated cellular apoptosis (24,29,30) but also the intracellular formation of MGO-AGEs. In terms of the mechanism by which retinal GLO-I is regulated, our previous study in retinal pericytes indicated a role for NO• (12). We now extend this finding to report that, in retinal vascular cells, candesartan reduces NO• levels, which is accompanied by the restoration of GLO-I. Overall, the present study provides new information about how Ang II interacts with the AGE pathway and the cellular mechanisms by which candesartan exerts its potent protective effects in diabetic retinopathy (Fig. 8).


Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function.

Miller AG, Tan G, Binger KJ, Pickering RJ, Thomas MC, Nagaraj RH, Cooper ME, Wilkinson-Berka JL - Diabetes (2010)

Proposed mechanism by which Ang II downregulates GLO-I in retinal vascular cells, leading to the generation of AGEs and vascular injury. The AT1-RB, Cand, is able to prevent diabetic retinal vascular injury by reducing nitric oxide and restoring GLO-I levels.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992784&req=5

Figure 8: Proposed mechanism by which Ang II downregulates GLO-I in retinal vascular cells, leading to the generation of AGEs and vascular injury. The AT1-RB, Cand, is able to prevent diabetic retinal vascular injury by reducing nitric oxide and restoring GLO-I levels.
Mentions: The present study provides novel evidence that GLO-I, an enzyme critical for retinal vascular cell survival (12), is downregulated by Ang II in the retina. Our findings are supported by evidence that the AT1-RB, candesartan, improves acellular capillary formation and inflammation in diabetic retinopathy with a concomitant restoration of retinal GLO-I expression and a reduction of MGO-AGEs and, in particular, the specific MGO-AGE argpyrimidine. These findings broaden the known actions of Ang II in the AGE pathway to include not only extracellular AGE-related events such as RAGE-mediated cellular apoptosis (24,29,30) but also the intracellular formation of MGO-AGEs. In terms of the mechanism by which retinal GLO-I is regulated, our previous study in retinal pericytes indicated a role for NO• (12). We now extend this finding to report that, in retinal vascular cells, candesartan reduces NO• levels, which is accompanied by the restoration of GLO-I. Overall, the present study provides new information about how Ang II interacts with the AGE pathway and the cellular mechanisms by which candesartan exerts its potent protective effects in diabetic retinopathy (Fig. 8).

Bottom Line: In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO(•)), the latter being a known negative regulator of GLO-I in BRP.In BREC and BRP, candesartan restored GLO-I and reduced NO(•).Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO-I.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia. antonia.miller@monash.edu

ABSTRACT

Objective: Advanced glycation end products (AGEs) and the renin-angiotensin system (RAS) are both implicated in the development of diabetic retinopathy. How these pathways interact to promote retinal vasculopathy is not fully understood. Glyoxalase-I (GLO-I) is an enzyme critical for the detoxification of AGEs and retinal vascular cell survival. We hypothesized that, in retina, angiotensin II (Ang II) downregulates GLO-I, which leads to an increase in methylglyoxal-AGE formation. The angiotensin type 1 receptor blocker, candesartan, rectifies this imbalance and protects against retinal vasculopathy.

Research design and methods: Cultured bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRP) were incubated with Ang II (100 nmol/l) or Ang II+candesartan (1 μmol/l). Transgenic Ren-2 rats that overexpress the RAS were randomized to be nondiabetic, diabetic, or diabetic+candesartan (5 mg/kg/day) and studied over 20 weeks. Comparisons were made with diabetic Sprague-Dawley rats.

Results: In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO(•)), the latter being a known negative regulator of GLO-I in BRP. In BREC and BRP, candesartan restored GLO-I and reduced NO(•). Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO-I. In diabetic Ren-2 rats, candesartan reduced retinal acellular capillaries, inflammation, and inducible nitric oxide synthase and NO(•), and restored GLO-I.

Conclusions: We have identified a novel mechanism by which candesartan improves diabetic retinopathy through the restoration of GLO-I.

Show MeSH
Related in: MedlinePlus