Yuzawa Yukio, Niki Ichiro, Kosugi Tomoki, Maruyama Shoichi, Yoshida Futoshi, Takeda Motohiro, Tagawa Yoshiaki, Kaneko Yukiko, Kimura Toshihide, Kato Noritoshi, Yamamoto Jyunichiro, Sato Waichi, Nakagawa Takahiko, Matsuo Seiichi
Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
J Am Soc Nephrol. 2008 Sep;19(9):1701-11. doi: 10.1681/ASN.2006121358. Epub 2008 Jun 4.
Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.
最近，血管内皮生长因子（VEGF）与一氧化氮解偶联所诱导的内皮功能障碍被认为与糖尿病肾病（DN）的发病机制有关。然而，由于缺乏模拟人类疾病的动物模型，对DN发病机制的研究受到了限制。在本报告中，对胰腺β细胞特异性钙调蛋白过表达转基因（CaMTg）小鼠这一潜在的DN新模型进行了表征，特别强调了VEGF及相关分子。CaMTg小鼠在3周时出现高血糖，3个月时出现持续性蛋白尿。形态计量分析显示肾小球和系膜区显著增大，伴有IV型胶原沉积。此外，还观察到了人类DN的病理特征（系膜溶解、Kimmelstiel-Wilson样结节性病变、渗出性病变以及伴有新生血管形成的入球和出球小动脉透明变性）。此外，VEGF表达增加与周细胞毛细血管数量增加有关。与非转基因小鼠相比，CaMTg小鼠肾脏中内皮型一氧化氮合酶的表达降低，而VEGF的表达显著升高。在CaMTg小鼠和非转基因小鼠的肾脏之间，未观察到VEGF受体-1或VEGF受体-2表达的差异。总之，CaMTg小鼠出现了人类DN的大多数特征性病变，在内皮型一氧化氮合酶表达降低的情况下VEGF表达升高可能导致内皮细胞增殖和功能障碍。该模型可能对DN发病机制和治疗的研究有用。
