Abstract
Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1+/−) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1+/− mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-κB p65 were significantly exacerbated in the diabetic VASH1+/− mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IκBα, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31+ endothelial area was also increased in the diabetic VASH1+/− mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-β1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1+/− mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy.
Highlights
Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease
The body weight (BW) was significantly lower and the HbA1c was significantly higher in all of the diabetic groups compared with the non-diabetic groups, and the diabetic VASH1+/2 mice did not show any significant differences in the BW, HbA1c, systolic blood pressure or serum creatinine compared with the diabetic wild-type mice (Table 1)
The reduction as well as the altered localization of nephrin and ZO-1, components of the slit diaphragm cell adhesion complexes [38], in the diabetic wild-type mice were significantly exacerbated in the diabetic VASH1+/2 mice, partly attributable to the increased albuminuria in these mice
Summary
Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. In the early stage of diabetic nephropathy, glomerular hyperfiltration, glomerular and tubular hypertrophy, microalbuminuria and thickening of the glomerular basement membrane (GBM) are observed. The involvement of the renin-angiotensin-aldosterone system, chemokines such as monocyte chemoattractant protein-1 (MCP-1)/CCL-2, transforming growth factor-b1 (TGF-b1) and advanced glycation end products in diabetic nephropathy has been reported [2,3]. The infiltration of macrophages is associated with diabetic nephropathy [4,5]. There are at least two types of macrophages, with the M1 macrophages being involved in promoting renal inflammation, and being a therapeutic target for renal disease. The other type is M2 macrophages, which are involved in the resolution of inflammation and repair of injury [6]
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