title: Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk.
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.
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and.
authors.forename: Leni
authors.initials: L
authors.lastname: Vandekerckhove
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and.
authors.forename: Zarha
authors.initials: Z
authors.lastname: Vermeulen
authors.affiliation: AG Nierengefäßphysiologie, Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Zhi Zhao
authors.initials: ZZ
authors.lastname: Liu
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and.
authors.forename: Sonia
authors.initials: S
authors.lastname: Boimvaser
authors.affiliation: AG Nierengefäßphysiologie, Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Patzak
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and.
authors.forename: Vincent F M
authors.initials: VF
authors.lastname: Segers
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and gilles.dekeulenaer@uantwerpen.be.
authors.forename: Gilles W
authors.initials: GW
authors.lastname: De Keulenaer
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001160:Arterioles / Q000187:drug effects; D002318:Cardiovascular Diseases; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D007678:Kidney Glomerulus / Q000187:drug effects; D050527:Mesangial Cells / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D020890:Neuregulin-1 / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects; D066247:Receptor, ErbB-4 / Q000187:drug effects; D011994:Recombinant Proteins; D012306:Risk; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D003094:Collagen; D007004:Hypoglycemic Agents; D007328:Insulin; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins; C094131:NRG1 protein, human; C524056:Erbb2 protein, mouse; C587690:Erbb4 protein, mouse
keywords: atherosclerosis; heart failure; nephropathy; neuregulin-1; type 1 diabetes