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


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.
Miller
Antonia G
AG
Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia. antonia.miller@monash.edu
Tan
Genevieve
G
Binger
Katrina J
KJ
Pickering
Raelene J
RJ
Thomas
Merlin C
MC
Nagaraj
Ram H
RH
Cooper
Mark E
ME
Wilkinson-Berka
Jennifer L
JL
D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology; D003930:Diabetic Retinopathy / Q000517:prevention & control*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D007328:Insulin / Q000627:therapeutic use; D007791:Lactoylglutathione Lyase / Q000187:drug effects / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D012160:Retina / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007328:Insulin; D012333:RNA, Messenger; C473112:Ren2 protein, mouse; D013777:Tetrazoles; D012083:Renin; D007791:Lactoylglutathione Lyase; C081643:candesartan