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

作者：Vandekerckhove, Leni; Vermeulen, Zarha; Liu, Zhi Zhao; Boimvaser, Sonia; Patzak, Andreas; Segers, Vincent F. M.; De Keulenaer, Gilles W.^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2016, 310(7): E495-E504.

DOI：10.1152/ajpendo.00432.2015

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

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. rh-NRG-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.

• 出版日期2016-4-1