Abstract：
Diabetic nephropathy remains the leading cause of end-stage kidney disease in many countries, and additional therapeutic targets are needed to prevent its development and progression. Some angiogenic factors are involved in the pathogenesis of diabetic nephropathy. Vasohibin-2 (VASH2) is a novel proangiogenic factor, and our previous study showed that glomerular damage is inhibited in diabetic Vash2 homozygous knockout mice. Therefore, we established a VASH2-targeting peptide vaccine as a tool for anti-VASH2 therapy in diabetic nephropathy. In this study, the preventive effects of the VASH2-targeting peptide vaccine against glomerular injury were examined in a streptozotocin (STZ)-induced diabetic mouse model. The mice were subcutaneously injected with the vaccine at two doses 2 wk apart and then intraperitoneally injected with 50 mg/kg STZ for 5 consecutive days. Glomerular injury was evaluated 20 wk after the first vaccination. Treatment with the VASH2-targeting peptide vaccine successfully induced circulating anti-VASH2 antibody without inflammation in major organs. Although the vaccination did not affect blood glucose levels, it significantly prevented hyperglycemia-induced increases in urinary albumin excretion and glomerular volume. The vaccination did not affect increased VASH2 expression but significantly inhibited renal angiopoietin-2 (Angpt2) expression in the diabetic mice. Furthermore, it significantly prevented glomerular macrophage infiltration. The preventive effects of vaccination on glomerular injury were also confirmed in db/db mice. Taken together, the results of this study suggest that the VASH2-targeting peptide vaccine may prevent diabetic glomerular injury in mice by inhibiting Angpt2-mediated microinflammation.NEW & NOTEWORTHY This study demonstrated preventive effects of VASH2-targeting peptide vaccine therapy on albuminuria and glomerular microinflammation in STZ-induced diabetic mouse model by inhibiting renal Angpt2 expression. The vaccination was also effective in db/db mice. The results highlight the importance of VASH2 in the pathogenesis of early-stage diabetic nephropathy and the practicability of anti-VASH2 strategy as a vaccine therapy.
摘要：
在许多国家，糖尿病肾病仍然是终末期肾病的主要原因，需要额外的治疗靶点来防止其发展和进展。一些血管生成因子参与了糖尿病肾病的发病机制。Vasohibin-2（VASH2）是一种新型的促血管生成因子，我们先前的研究表明，糖尿病Vash2纯合基因敲除小鼠的肾小球损伤受到抑制。因此,我们建立了VASH2靶向肽疫苗,作为糖尿病肾病抗VASH2治疗的工具.在这项研究中,在链脲佐菌素(STZ)诱导的糖尿病小鼠模型中,研究了VASH2靶向肽疫苗对肾小球损伤的预防作用.以间隔2周的两个剂量对小鼠皮下注射疫苗,然后连续5天腹膜内注射50mg/kgSTZ。在第一次接种疫苗后20周评估肾小球损伤。用VASH2靶向肽疫苗治疗成功地诱导循环抗VASH2抗体,而在主要器官中没有炎症。虽然接种疫苗不会影响血糖水平，它显著阻止了高血糖引起的尿白蛋白排泄和肾小球体积增加.疫苗接种不影响增加的VASH2表达,但显著抑制糖尿病小鼠中的肾血管生成素-2(Angpt2)表达。此外，它显著防止肾小球巨噬细胞浸润。在db/db小鼠中也证实了疫苗接种对肾小球损伤的预防作用。一起来看,这项研究的结果表明,VASH2靶向肽疫苗可能通过抑制Angpt2介导的微炎症来预防小鼠糖尿病性肾小球损伤.
