Vandekerckhove L, Vermeulen Z, Liu ZZ, Boimvaser S, Patzak A, Segers VF, De Keulenaer GW. Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk. Am J Physiol Endocrinol Metab 310: E495-E504, 2016. First published January 19, 2016 doi:10.1152/ajpendo.00432.2015 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 Ϫ/Ϫ ) 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 Ϫ/Ϫ mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE Ϫ/Ϫ littermates. Vehicle-treated diabetic apoE Ϫ/Ϫ 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.
This work investigates the degradation of PLGA implants in an aqueous medium maintained at physiological pH & 7.4. Two limiting systems are also investigated, which involve the degradation of PLGA microspheres in two different media characterized by: (i) a non-regulated pH, for emulating the autocatalyzed degradation in the implant core; and (ii) a regulated physiological pH, for emulating the uncatalyzed degradation at the implant surface. The degradation experiments were carried out along 40-50 days, and samples withdrawn during this period were characterized by gravimetry, electronic microscopy, and size exclusion chromatography. Experimental results suggest that PLGA implants are degraded according to a time-variant spatial pattern, which depends on the pH of the surrounding medium. Initially, the implants suffered a typically bulk erosion process, governed by the acidification of the implant core; and after breakage of the implant wall, the regulated physiological pH induces a surface erosion process. The two auxiliary microsphere-based experiments were useful to elucidate the degradation phenomena occurring in the PLGA implants. The evolution of the mass loss and the weight-average molecular weight along the degradation can be successfully predicted by simple mathematical models based on first-order kinetics.
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