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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

NO• levels in BREC (A) and BRP (B) after treatment with Ang II and Cand for 24 h. A: Treatment of BREC with 100 nmol/l Ang II had no effect on NO• levels. In BREC treated with Ang II+Cand (1 μmol/l), NO• levels were reduced below both control and Ang II treated cells. *P < 0.01 versus control, †P < 0.03 versus Ang II. B: Treatment of BRP with 100 nmol/l Ang II significantly increased NO• levels. In BRP treated with Ang II+Cand, NO• levels were reduced to control levels. *P < 0.05 versus control, †P < 0.05 versus Ang II. BRP were analyzed by one-way ANOVA, followed by Bonferroni post hoc tests. BREC were analyzed by Kruskal-Wallis tests followed by Mann-Whitney U tests. Values are the means of 3 and 7 independent experiments (BRP and BREC, respectively) with triplicate samples within each experiment.
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Figure 3: NO• levels in BREC (A) and BRP (B) after treatment with Ang II and Cand for 24 h. A: Treatment of BREC with 100 nmol/l Ang II had no effect on NO• levels. In BREC treated with Ang II+Cand (1 μmol/l), NO• levels were reduced below both control and Ang II treated cells. *P < 0.01 versus control, †P < 0.03 versus Ang II. B: Treatment of BRP with 100 nmol/l Ang II significantly increased NO• levels. In BRP treated with Ang II+Cand, NO• levels were reduced to control levels. *P < 0.05 versus control, †P < 0.05 versus Ang II. BRP were analyzed by one-way ANOVA, followed by Bonferroni post hoc tests. BREC were analyzed by Kruskal-Wallis tests followed by Mann-Whitney U tests. Values are the means of 3 and 7 independent experiments (BRP and BREC, respectively) with triplicate samples within each experiment.

Mentions: To determine whether Ang II's downregulation of GLO-I involves NO•, we measured NO• production in BREC and BRP after Ang II treatment in the presence or absence of candesartan. In BREC, Ang II had no effect on NO• levels, whereas in BRP, Ang II increased NO• production 1.2-fold. In both cell types, candesartan reduced NO• levels in Ang II-treated cells compared with those only receiving Ang II (Fig. 3).


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)

NO• levels in BREC (A) and BRP (B) after treatment with Ang II and Cand for 24 h. A: Treatment of BREC with 100 nmol/l Ang II had no effect on NO• levels. In BREC treated with Ang II+Cand (1 μmol/l), NO• levels were reduced below both control and Ang II treated cells. *P < 0.01 versus control, †P < 0.03 versus Ang II. B: Treatment of BRP with 100 nmol/l Ang II significantly increased NO• levels. In BRP treated with Ang II+Cand, NO• levels were reduced to control levels. *P < 0.05 versus control, †P < 0.05 versus Ang II. BRP were analyzed by one-way ANOVA, followed by Bonferroni post hoc tests. BREC were analyzed by Kruskal-Wallis tests followed by Mann-Whitney U tests. Values are the means of 3 and 7 independent experiments (BRP and BREC, respectively) with triplicate samples within each experiment.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: NO• levels in BREC (A) and BRP (B) after treatment with Ang II and Cand for 24 h. A: Treatment of BREC with 100 nmol/l Ang II had no effect on NO• levels. In BREC treated with Ang II+Cand (1 μmol/l), NO• levels were reduced below both control and Ang II treated cells. *P < 0.01 versus control, †P < 0.03 versus Ang II. B: Treatment of BRP with 100 nmol/l Ang II significantly increased NO• levels. In BRP treated with Ang II+Cand, NO• levels were reduced to control levels. *P < 0.05 versus control, †P < 0.05 versus Ang II. BRP were analyzed by one-way ANOVA, followed by Bonferroni post hoc tests. BREC were analyzed by Kruskal-Wallis tests followed by Mann-Whitney U tests. Values are the means of 3 and 7 independent experiments (BRP and BREC, respectively) with triplicate samples within each experiment.
Mentions: To determine whether Ang II's downregulation of GLO-I involves NO•, we measured NO• production in BREC and BRP after Ang II treatment in the presence or absence of candesartan. In BREC, Ang II had no effect on NO• levels, whereas in BRP, Ang II increased NO• production 1.2-fold. In both cell types, candesartan reduced NO• levels in Ang II-treated cells compared with those only receiving Ang II (Fig. 3).

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