Valsartan but not atenolol improves vascular pathology in diabetic Ren-2 rat retina.
BACKGROUND
To determine whether angiotensin type 1 receptor blockade (AT1-RB) or antihypertensive therapy per se, attenuates acellular capillaries and proliferating endothelial cells in the retina of diabetic Ren-2 rats.


METHODS
Eight-week-old hypertensive Ren-2 rats were made diabetic (streptozotocin, 55 mg/kg) or nondiabetic (0.1 mol/L citrate buffer) and studied for 20 weeks. Diabetic Ren-2 rats received by gavage the AT1-RB valsartan at 4, 10, or 40 mg/kg/d or the beta1-adrenergic receptor blocker atenolol at 30 mg/kg/d. Systolic blood pressure (BP) was measured every 4 weeks. Acellular capillaries (devoid of pericytes and endothelial cells) were counted on trypsin digests. Proliferating endothelial cells were evaluated using double immunolabeling for isolectin and proliferating cell nuclear antigen.


RESULTS
Systolic BP was unchanged in control Ren-2 rats throughout the study (186.6 +/- 3.5 mm Hg, nondiabetic; 185.0 +/- 0.7 mm Hg, diabetic; week 20). In diabetic Ren-2 rats, 4 and 10 mg of valsartan and atenolol reduced systolic BP to a similar extent, and at 20 weeks were comparable to diabetic Sprague Dawley rats (123.0 +/- 1.4 mm Hg). In diabetic Ren-2 rats, 40 mg of valsartan reduced systolic BP (110.9 +/- 1.1 mm Hg, 20 weeks) below that of Sprague Dawley rats. Acellular capillaries and proliferating endothelial cells were increased by 3- and 1.6-fold, respectively, in diabetic Ren-2 controls and reduced with 4 and 10 mg of valsartan and further reduced with 40 mg of valsartan. Atenolol had no effect on retinal pathology in diabetic Ren-2 rats.


CONCLUSIONS
Blockade of the renin-angiotensin system but not antihypertensive therapy with atenolol reduces vascular pathology in diabetic Ren-2 retina, suggesting that angiotensin II is a causative factor and therapeutic target in diabetic retinopathy.
Wilkinson-Berka
Jennifer Louise
JL
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia. Jennifer.Wilkinson-Berka@med.monash.edu.au
Tan
Genevieve
G
Jaworski
Kassie
K
Ninkovic
Slavisa
S
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D001262:Atenolol / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood / Q000235:genetics* / Q000502:physiology; D012171:Retinal Vessels / Q000473:pathology* / Q000503:physiopathology; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D001262:Atenolol; D006442:Glycated Hemoglobin; D012083:Renin; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; C473112:Ren2 protein, mouse