Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions
Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions
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DOI：
10.1681/asn.2006010075
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发表时间：
2007-07-01
影响因子：
13.6
通讯作者：
Fan, Jianglin
中科院分区：
文献类型：
--
作者：
Liu, Enqi;Morimoto, Masatoshi;Fan, Jianglin
血管内皮生长因子（VEGF）是维持正常肾功能的重要介质。此外，一些证据表明肾小球中VEGF的上调可能与肾功能不全如糖尿病肾病相关或引起肾功能不全如糖尿病肾病。为了阐明肾小球中高水平VEGF的病理后果，产生并表征了在人α-l-抗胰蛋白酶启动子控制下在肾和肝中表达人VEGF α，β同种型的转基因（Tg）兔。用8 ~ 55周龄的杂合子Tg兔及其同窝仔兔，研究了肾功能和结构。与对照组相比，Tg兔出现进行性蛋白尿，早期肾小球滤过率升高，晚期肾小球滤过率降低。组织学检查显示，Tg兔肾脏的特点是相当大的肾小球肥大的结果增加的增殖肾小球毛细血管和肾小球系膜细胞伴随着突出的足细胞肥大。从20周龄开始，随着年龄的增长，Tg兔肾脏显示出明显的微动脉瘤形成和血管极区毛细血管增生。在后期（55周），许多肾小球显示硬化和簇状塌陷，在肾小管萎缩和间质纤维化的背景下形成肾小球囊肿。本研究首次提供证据表明，肾小球中VEGF表达增加直接导致与蛋白尿相关的肾小球肥大，表明VEGF对肾小球病理生理过程发挥多种作用。
Vascular endothelial growth factor (VEGF) is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence suggest that upregulation of VEGF in glomeruli may be associated with or cause renal dysfunction such as diabetic nephropathy. For elucidation of the pathologic consequences of high levels of VEGF in glomeruli, transgenic (Tg) rabbits that express human VEGF,,, isoform in both kidney and liver under the control of the human a-l-antitrypsin promoter were generated and characterized. With the use of heterozygous Tg rabbits and their littermates aged 8 to 55 wk, renal functions and structures were investigated. Compared with control rabbits, Tg rabbits exhibited progressive proteinuria with increased GFR at the early stage and decreased GFR at the later stage. Histologic examinations revealed that Tg rabbit kidneys were characterized by considerable glomerular hypertrophy as a result of increased proliferation of both glomerular capillaries and mesangial cells accompanied by prominent podocyte hypertrophy. With increasing age starting from 20 wk, Tg rabbit kidneys showed prominent formation of microaneurysms and capillary proliferation at the vascular pole area. At a later stage (55 wk), many glomeruli showed sclerosis and tuft collapse with the formation of glomerular cysts on a background of tubular atrophy and interstitial fibrosis. This study provides the first evidence that increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria, suggesting that VEGF exerts multiple effects on the glomerular pathophysiologic processes.