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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<jats:sup>\u2212\/\u2212<\/jats:sup>) 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<jats:sup>\u2212\/\u2212<\/jats:sup> mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE<jats:sup>\u2212\/\u2212<\/jats:sup> littermates. Vehicle-treated diabetic apoE<jats:sup>\u2212\/\u2212<\/jats:sup> 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. <\/jats:p>","DOI":"10.1152\/ajpendo.00432.2015","type":"journal-article","created":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T23:54:24Z","timestamp":1453247664000},"page":"E495-E504","source":"Crossref","is-referenced-by-count":44,"title":["Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk"],"prefix":"10.1152","volume":"310","author":[{"given":"Leni","family":"Vandekerckhove","sequence":"first","affiliation":[{"name":"Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zarha","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi Zhao","family":"Liu","sequence":"additional","affiliation":[{"name":"AG Nierengef\u00e4\u00dfphysiologie, Institut f\u00fcr Vegetative Physiologie, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Boimvaser","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Patzak","sequence":"additional","affiliation":[{"name":"AG Nierengef\u00e4\u00dfphysiologie, Institut f\u00fcr Vegetative Physiologie, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent F. 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