Overexpression of calmodulin in pancreatic β cells induces diabetic nephropathy

Yukio Yuzawa, Ichiro Niki, Tomoki Kosugi, Shoichi Maruyama, Futoshi Yoshida, Motohiro Takeda, Yoshiaki Tagawa, Yukiko Kaneko, Toshihide Kimura, Noritoshi Kato, Jyunichiro Yamamoto, Waichi Sato, Takahiko Nakagawa, Seiichi Matsuo

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Abstract

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 β 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.

Original languageEnglish
Pages (from-to)1701-1711
Number of pages11
JournalJournal of the American Society of Nephrology
Volume19
Issue number9
DOIs
Publication statusPublished - 01-09-2008

All Science Journal Classification (ASJC) codes

  • Nephrology

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    Yuzawa, Y., Niki, I., Kosugi, T., Maruyama, S., Yoshida, F., Takeda, M., Tagawa, Y., Kaneko, Y., Kimura, T., Kato, N., Yamamoto, J., Sato, W., Nakagawa, T., & Matsuo, S. (2008). Overexpression of calmodulin in pancreatic β cells induces diabetic nephropathy. Journal of the American Society of Nephrology, 19(9), 1701-1711. https://doi.org/10.1681/ASN.2006121358