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Title
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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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Author
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Abstract
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| Neuregulin-1 (NRG-1) is an endothelium-derived growth factor with cardioprotective and anti-atherosclerotic properties, and is currently tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often co-exists with renal failure, sharing an overlapping pathophysiogical background. In this study, we hypothesized that NRG-1 may 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 weeks and were compared with non-diabetic 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, 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 Ang II-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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Language
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English
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Source (journal)
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American journal of physiology: endocrinology and metabolism / American Physiological Society. - Bethesda, Md
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Publication
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Bethesda, Md
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2016
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ISSN
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0193-1849
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DOI
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10.1152/AJPENDO.00432.2015
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Volume/pages
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310
:7
(2016)
, p. E495-E504
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ISI
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000373272900003
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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