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Experimental Biology and Medicine 231:1030-1033 (2006)
© 2006 Society for Experimental Biology and Medicine

ENDOCRINE AND DIABETES MELLITUS

Downregulation of Renal Endothelin-Converting Enzyme 2 Expression in Early Autoimmune Diabetes

Jana Ortmann*,1, Philipp C. Nett*,{ddagger},1, Jennifer Celeiro*, Regina Hofmann-Lehmann{dagger}, Luigi Tornillo§, Luigi M. Terracciano§ and Matthias Barton*,2

* Medical Policlinic, Department of Internal Medicine, University Hospital Zürich, and {dagger} Clinical Laboratory, Vetsuisse-Faculty, University of Zürich, CH-8091 Zürich, Switzerland; {ddagger} Department of Visceral and Transplant Surgery, University Hospital Bern, CH-3010 Bern, Switzerland; and § Institute of Pathology, University Hospital Basel, CH-4031 Basel, Switzerland

To whom requests for reprints should be addressed at 2 Medizinische Poliklinik, Departement für Innere Medizin, Universitätsspital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: barton{at}usz.ch

Abstract

To determine whether renal expression of endothelin-converting enzymes (ECEs) and endothelin (ET) is affected in the early stages of autoimmune diabetes mellitus and whether ETA receptors are involved, prediabetic nonobese diabetic (NOD) and control mice were treated with the ETA receptor antagonist BSF461314 (a follow-up compound of darusentan) or with placebo. Blood samples were analyzed for glucose levels, and renal gene expression of ECE-1, ECE-2, and prepro-ET-1 was determined using real-time polymerase chain reaction. Renal morphology was assessed using standard histologic techniques. ECE-1, ECE-2, and prepro-ET-1 mRNA was detected in the kidneys of NOD and control mice. Despite normal renal histology, expression of ECE-1 and prepro-ET-1 was reduced in NOD mice by approximately 50% compared with controls (P < 0.01); ECE-2 was markedly decreased by almost 90% compared with controls (P < 0.001). Treatment with BSF461314 for 6 weeks delayed the onset of diabetes (P < 0.05) and increased expression of all three genes (P < 0.05) in NOD mice only. Hyperglycemia at an early stage of autoimmune diabetes is associated with transcriptional downregulation of ECE-1, ECE-2, and prepro-ET-1 in the kidney. Blockade of ETA receptors inhibits diabetes-associated gene regulation and delays the onset of diabetes, suggesting its therapeutic potential for the treatment of autoimmune forms of diabetes.

Key Words: BSF461314 • darusentan • glomerulosclerosis • hyperglycemia • inflammation • kidney • pathology






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