Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
American journal of physiology: endocrinology and metabolism / American Physiological Society. - Bethesda, Md
, p. E495-E504
University of Antwerp
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.