Abstract
Angiogenesis has been implicated in glomerular alterations in the early stage of diabetic nephropathy. We previously reported the renoprotective effects of vasohibin-1 (VASH1), which is a novel angiogenesis inhibitor derived from endothelial cells, on diabetic nephropathy progression. Vasohibin-2 (VASH2) was originally identified as a VASH1 homolog and possesses pro-angiogenic activity in contrast to VASH1. In addition, VASH2 was recently shown to promote epithelial-to-mesenchymal transition via enhanced transforming growth factor (TGF)-β signaling in cancer cells. Herein, we investigated the pathogenic roles of VASH2 in diabetic nephropathy using VAHS2-deficient mice. The type 1 diabetes model was induced by intraperitoneal injections of streptozotocin in VASH2 homozygous knockout (VASH2LacZ/LacZ) or wild-type mice. These mice were euthanized 16 weeks after inducing hyperglycemia. Increased urine albumin excretion and creatinine clearance observed in diabetic wild-type mice were significantly prevented in diabetic VASH2-deficient mice. Accordingly, diabetes-induced increase in glomerular volume and reduction in glomerular slit-diaphragm density were significantly improved in VASH2 knockout mice. Increased glomerular endothelial area was also suppressed in VASH2-deficient mice, in association with inhibition of enhanced vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), but not VEGF level. Furthermore, glomerular accumulation of mesangial matrix, including type IV collagen, and increased expression of TGF-β were improved in diabetic VASH2 knockout mice compared with diabetic wild-type mice. Based on the immunofluorescence findings, endogenous VASH2 localization in glomeruli was consistent with mesangial cells. Human mesangial cells (HMCs) were cultured under high glucose condition in in vitro experiments. Transfection of VASH2 small interfering RNA (siRNA) into the HMCs resulted in the suppression of type IV collagen production induced by high glucose compared with control siRNA. These results indicate that VASH2 may be involved in diabetes-induced glomerular alterations, particularly impaired filtration barrier and mesangial expansion. Therefore, VASH2 is likely to represent a promising therapeutic target for diabetic nephropathy.
Highlights
Diabetic nephropathy is a leading cause of end-stage kidney disease (ESKD) in developed countries
STZ-induced diabetes resulted in significantly increased hemoglobin A1c (HbA1c) and, systolic blood pressure (SBP), and body weight (BW) loss, but did not change the serum creatinine level
VASH2-deficiency did not affect BW, SBP, HbA1c, and serum creatinine (sCr) compared with WT mice
Summary
Diabetic nephropathy is a leading cause of end-stage kidney disease (ESKD) in developed countries. Despite advances in understanding the molecular mechanisms involving the development and progression of diabetic nephropathy, such as advanced glycation end-products, protein kinase C, and transforming growth factor-β (TGF-β) [2], certain effective therapeutic strategies remain to be established. Excessive activation of glomerular VEGF signaling in mice has been shown to cause mesangial matrix expansion, resembling diabetic nephropathy [6, 7]. Since the landmark study that revealed the renoprotective efficacy of anti-VEGF antibody in diabetic mice [8], anti-angiogenic strategies remain possible options for diabetic nephropathy treatment. Considering the possibility that anti-angiogenic strategies could suppress glomerular lesions in diabetes, including increased capillary area and mesangial expansion, novel angiogenic factors involved in the pathogenesis of diabetic nephropathy are likely to become promising therapeutic targets
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