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ENDOCRINE AND DIABETES MELLITUS

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

Jana Ortmann^*,1, Philipp C. Nett^*,,1, Jennifer Celeiro^*, Regina Hofmann-Lehmann, Luigi Tornillo, Luigi M. Terracciano and Matthias Barton^*,2

^* Medical Policlinic, Department of Internal Medicine, University Hospital Zürich, and Clinical Laboratory, Vetsuisse-Faculty, University of Zürich, CH-8091 Zürich, Switzerland; 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 ET_A receptors are involved, prediabetic nonobese diabetic (NOD) and control mice were treated with the ET_A 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 ET_A 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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