Induction of progressive glomerulonephritis by podocyte-specific overexpression of platelet-derived growth factor-D.
Induction of progressive glomerulonephritis by podocyte-specific overexpression of platelet-derived growth factor-D.
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DOI：
10.1038/ki.2011.278
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发表时间：
2011-12
影响因子：
19.6
通讯作者：
Claudia R C van Roeyen;F. Eitner;P. Boor;M. Moeller;U. Raffetseder;Lydia Hanssen;Eva Bücher;L. Villa;M. Banas;K. Hudkins;C. Alpers;T. Ostendorf;J. Floege
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作者：
Claudia R C van Roeyen;F. Eitner;P. Boor;M. Moeller;U. Raffetseder;Lydia Hanssen;Eva Bücher;L. Villa;M. Banas;K. Hudkins;C. Alpers;T. Ostendorf;J. Floege
血小板衍生生长因子-d (PDGF-D)，通常在足细胞中表达，在体内介导系膜细胞增殖。为了进一步研究这一点，我们创建了足细胞特异性过表达PDGF-D的转基因小鼠。在11个月大时，半合子小鼠与野生型幼崽基本无法区分；然而，4周以上的半合子小鼠通常表现出肾小球簇内细胞增殖增加。许多半合子小鼠还出现广泛的节段性肾小球硬化和局灶性毛细血管外增生，伴纤维蛋白/纤维蛋白原沉积，广泛的小管间质损伤，蛋白尿和肾功能不全。电镜观察发现病灶足突消失。与野生型小鼠相比，半合子小鼠的肾足细胞缺失和/或去分化，足细胞中足细胞素和肾素mRNA表达以及肾小球wt -1阳性细胞数量显著减少。PDGF- d转基因小鼠肾皮质中PDGF- a、-B及两种PDGF受体链mrna、纤维连接蛋白、IV型胶原蛋白、RANTES、MCP-1和CCR-2 mrna均升高。只有8.5%的新生小鼠是纯合子过表达者，4周时的死亡率为37%。因此，足细胞特异性的PDGF-D过表达可引起系血管增生性疾病、肾小球硬化和月牙状肾小球肾炎。因此，足细胞特异性生长因子过表达可诱导滤过流上游旁分泌系膜细胞增殖。
Platelet-derived growth factor-D (PDGF-D), normally expressed in podocytes, mediates mesangial cell proliferationin vivo. To study this further, we created transgenic mice with podocyte-specific overexpression of PDGF-D. Hemizygous mice were grossly indistinguishable from wild-type littermates through 11 months of age; however, hemizygous mice older than 4 weeks commonly exhibited increased cell proliferation within the glomerular tuft. Many hemizygous mice also developed widespread segmental glomerulosclerosis and focal extracapillary proliferation with fibrin/fibrinogen deposition, extensive tubulointerstitial damage, proteinuria, and renal insufficiency. Electron microscopy found focal foot process effacement. Renal mRNA expression of podocin and nephrin, as well as the number of glomerular WT-1-positive cells, were significantly reduced in hemizygous compared to wild-type mice, indicating loss and/or dedifferentation of podocytes. PDGF-A, -B, and both PDGF receptor chain mRNAs, fibronectin, type IV collagen, RANTES, MCP-1, and CCR-2 mRNAs were all increased in the renal cortex of PDGF-D transgenic mice. Only 8.5% of newborn mice were homozygous overexpressors exhibiting a mortality rate of 37% at 4 weeks. Thus, podocyte-specific overexpression of PDGF-D caused mesangioproliferative disease, glomerulosclerosis, and crescentic glomerulonephritis. Hence, podocyte-specific growth factor overexpression can induce paracrine mesangial cell proliferation upstream of the filtration flow.