title: Endothelin antagonism prevents diabetic retinopathy in NOD mice: a potential role of the angiogenic factor adrenomedullin.
abstract: Altered activity of retinal endothelin-1 (ET-1) and nitric oxide may play a causal role in the hemodynamic and histopathological changes of diabetic retinopathy. This study evaluated the therapeutic potential of long-term selective blockade of the ET-1(A) receptor (ETRA) to prevent the development of retinopathy in a genetic mouse model of nonobese type 1 diabetes (NOD). Mice with NOD that received subcutaneous implantation of insulin pellets and wild-type control mice were treated for 4 months with the selective ETRA antagonist LU208075 (30 mg/kg/day) via drinking water. At the end of the study, blood glucose levels were evaluated, and animals were anesthetized and perfused intracardially with FITC-labeled dextran. Retinas were removed and either fixed in formalin for confocal microscope evaluation of retinal vascular filling or transferred to RNALater for quantitative reverse transcriptase-polymerase chain reaction to evaluate expression of NOS-3, NOS-1, ET-1, ETRA, ETRB, and the angiogenic factor adrenomedullin. Compared with wild-type controls, expression of ET-1, ETRA, ETRB, and adrenomedullin in mice with NOD were markedly upregulated in the retinas of nontreated mice (cycle time values relative to GAPDH [deltaCt], 14.8 vs. 13.7, 18.57 vs. 17.5, 10.76 vs. 9.9, and 11.7 vs. 9.1, respectively). Mean integral fluorescence intensity (MIFI) of retinal vascular filling was reduced from normal values of 24 to 12.5 in nontreated animals. LU208075 treatment normalized the upregulated expression of ET-1 and adrenomedullin, as well as the deficit in MIFI, but did not affect the increased ETRA and ETRB expression or the elevated plasma glucose levels found in nontreated animals. NOS isoform expression was essentially unchanged. ETRA antagonists may provide a novel therapeutic strategy to slow or prevent progression of retinal microvascular damage and proliferation in patients for whom there is clear evidence of activation of the ET-1 system.
authors.affiliation: Department of Clinical Experimental Research, University of Bern, Bern, CH-3010 Switzerland. sidney.shaw@dkf.unibe.ch
authors.forename: Sidney G
authors.initials: SG
authors.lastname: Shaw
authors.forename: Jane P
authors.initials: JP
authors.lastname: Boden
authors.forename: Erwin
authors.initials: E
authors.lastname: Biecker
authors.forename: Juerg
authors.initials: J
authors.lastname: Reichen
authors.forename: Barbara
authors.initials: B
authors.lastname: Rothen
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003930:Diabetic Retinopathy / Q000517:prevention & control*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology; D011724:Pyridazines; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D010666:Phenylpropionates; D011724:Pyridazines; D014665:Vasodilator Agents; D053607:Adrenomedullin; C467894:ambrisentan