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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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

Fingerprint

Diabetic Nephropathies
Calmodulin
Vascular Endothelial Growth Factor A
Transgenic Mice
Vascular Endothelial Growth Factor Receptor-1
Kidney
Vascular Endothelial Growth Factor Receptor-2
Collagen Type IV
Nitric Oxide Synthase Type III
Proteinuria
Hyperglycemia
Oxidoreductases
Nitric Oxide
Animal Models
Arteries

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

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. / Overexpression of calmodulin in pancreatic β cells induces diabetic nephropathy. In: Journal of the American Society of Nephrology. 2008 ; Vol. 19, No. 9. pp. 1701-1711.
@article{e7f7923ea7b94f248e75c141bdcfd5be,
title = "Overexpression of calmodulin in pancreatic β cells induces diabetic nephropathy",
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.",
author = "Yukio Yuzawa and Ichiro Niki and Tomoki Kosugi and Shoichi Maruyama and Futoshi Yoshida and Motohiro Takeda and Yoshiaki Tagawa and Yukiko Kaneko and Toshihide Kimura and Noritoshi Kato and Jyunichiro Yamamoto and Waichi Sato and Takahiko Nakagawa and Seiichi Matsuo",
year = "2008",
month = "9",
day = "1",
doi = "10.1681/ASN.2006121358",
language = "English",
volume = "19",
pages = "1701--1711",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "9",

}

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, vol. 19, no. 9, pp. 1701-1711. https://doi.org/10.1681/ASN.2006121358

Overexpression of calmodulin in pancreatic β cells induces diabetic nephropathy. / 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.

In: Journal of the American Society of Nephrology, Vol. 19, No. 9, 01.09.2008, p. 1701-1711.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Overexpression of calmodulin in pancreatic β cells induces diabetic nephropathy

AU - Yuzawa, Yukio

AU - Niki, Ichiro

AU - Kosugi, Tomoki

AU - Maruyama, Shoichi

AU - Yoshida, Futoshi

AU - Takeda, Motohiro

AU - Tagawa, Yoshiaki

AU - Kaneko, Yukiko

AU - Kimura, Toshihide

AU - Kato, Noritoshi

AU - Yamamoto, Jyunichiro

AU - Sato, Waichi

AU - Nakagawa, Takahiko

AU - Matsuo, Seiichi

PY - 2008/9/1

Y1 - 2008/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=54749108433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54749108433&partnerID=8YFLogxK

U2 - 10.1681/ASN.2006121358

DO - 10.1681/ASN.2006121358

M3 - Article

C2 - 18525005

AN - SCOPUS:54749108433

VL - 19

SP - 1701

EP - 1711

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 9

ER -