title: Downregulation of renal endothelin-converting enzyme 2 expression in early autoimmune diabetes.
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.
authors.affiliation: Medical Policlinic, Department of Internal Medicine, University Hospital Zürich, Switzerland.
authors.forename: Jana
authors.initials: J
authors.lastname: Ortmann
authors.forename: Philipp C
authors.initials: PC
authors.lastname: Nett
authors.forename: Jennifer
authors.initials: J
authors.lastname: Celeiro
authors.forename: Regina
authors.initials: R
authors.lastname: Hofmann-Lehmann
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology*; D015536:Down-Regulation; D065130:Endothelin A Receptor Antagonists; D000072396:Endothelin-Converting Enzymes; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D007668:Kidney / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D013997:Time Factors
chemical_list: D065130:Endothelin A Receptor Antagonists; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; C000606926:Ece2 protein, mouse; D000072396:Endothelin-Converting Enzymes