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      Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

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          Abstract

          Neuregulin-1 (NRG-1) is an endothelium-derived growth factor with cardioprotective and antiatherosclerotic properties and is currently being tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often coexists with renal failure, sharing an overlapping pathophysiological background. In this study, we hypothesized that NRG-1 might protect against cardiomyopathy, atherosclerosis, and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (apoE −/−) type 1 diabetes mouse model prone to the development of cardiomyopathy, atherosclerosis, and nephropathy and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia induced by streptozotocin, apoE −/− mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE −/− littermates. Vehicle-treated diabetic apoE −/− mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques, and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin (NGAL), upregulation of renal fibrotic markers, and glomerulosclerosis. rhNRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys and prevented LV dilatation, improved LV contractile function, and reduced atherosclerotic plaque size. rhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis, and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro but did not affect AngII-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys.

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          Author and article information

          Journal
          Am J Physiol Endocrinol Metab
          Am. J. Physiol. Endocrinol. Metab
          ajpendo
          ajpendo
          AJPENDO
          American Journal of Physiology - Endocrinology and Metabolism
          American Physiological Society (Bethesda, MD )
          0193-1849
          1522-1555
          19 January 2016
          1 April 2016
          1 April 2017
          : 310
          : 7
          : E495-E504
          Affiliations
          [1] 1Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and
          [2] 2AG Nierengefäßphysiologie, Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
          Author notes
          Address for reprint requests and other correspondence: G. W. De Keulenaer, University of Antwerp, CDE, Universiteitsplein 1, T2.30, 2610 Wilrijk, Belgium (e-mail: gilles.dekeulenaer@ 123456uantwerpen.be ).
          Article
          PMC4824141 PMC4824141 4824141 E-00432-2015
          10.1152/ajpendo.00432.2015
          4824141
          26786778
          5413fd65-fe44-4fa2-9ce0-867d7cc58200
          Copyright © 2016 the American Physiological Society
          History
          : 7 October 2015
          : 8 January 2016
          Funding
          Funded by: Fond voor wetenschappelijk onderzoek
          Award ID: G0C5214
          Funded by: European Commission
          Award ID: FP7-HEALTH-F2-2010-261409
          Funded by: IOF-POC University of Antwerp
          Award ID: #FFI150002
          Funded by: DeHousse mandate
          Funded by: Amidila postdoctoral fellowship Erasmus Mundus
          Categories
          Articles

          neuregulin-1,type 1 diabetes,heart failure,atherosclerosis,nephropathy

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