Overexpression of calmodulin in pancreatic beta cells induces diabetic nephropathy.
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.
Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. yukio@med.nagoya-u.ac.jp
Yukio
Y
Yuzawa
Ichiro
I
Niki
Tomoki
T
Kosugi
Shoichi
S
Maruyama
Futoshi
F
Yoshida
Motohiro
M
Takeda
Yoshiaki
Y
Tagawa
Yukiko
Y
Kaneko
Toshihide
T
Kimura
Noritoshi
N
Kato
Jyunichiro
J
Yamamoto
Waichi
W
Sato
Takahiko
T
Nakagawa
Seiichi
S
Matsuo
D000818:Animals; D001160:Arterioles / Q000473:pathology; D002147:Calmodulin / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000097:blood / Q000473:pathology* / Q000652:urine; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002147:Calmodulin; D018180:Thrombomodulin; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D040262:Receptors, Vascular Endothelial Growth Factor