Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy

Takahiko Nakagawa, Waichi Sato, Olena Glushakova, Marcelo Heinig, Tracy Clarke, Martha Campbell-Thompson, Yukio Yuzawa, Mark A. Atkinson, Richard J. Johnson, Byron Croker

Research output: Contribution to journalArticle

252 Citations (Scopus)

Abstract

The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.

Original languageEnglish
Pages (from-to)539-550
Number of pages12
JournalJournal of the American Society of Nephrology
Volume18
Issue number2
DOIs
Publication statusPublished - 01-02-2007
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type III
Diabetic Nephropathies
Knockout Mice
Vascular Endothelial Growth Factor A
Nitric Oxide
Endothelial Cells
Cell Proliferation
Advanced Glycosylation End Products
Albuminuria
Uric Acid
Oxidants
C-Reactive Protein
Renal Insufficiency
Homeostasis
Animal Models
Insulin
Hypertension
Glucose
Mortality

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Nakagawa, T., Sato, W., Glushakova, O., Heinig, M., Clarke, T., Campbell-Thompson, M., ... Croker, B. (2007). Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. Journal of the American Society of Nephrology, 18(2), 539-550. https://doi.org/10.1681/ASN.2006050459
Nakagawa, Takahiko ; Sato, Waichi ; Glushakova, Olena ; Heinig, Marcelo ; Clarke, Tracy ; Campbell-Thompson, Martha ; Yuzawa, Yukio ; Atkinson, Mark A. ; Johnson, Richard J. ; Croker, Byron. / Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. In: Journal of the American Society of Nephrology. 2007 ; Vol. 18, No. 2. pp. 539-550.
@article{a8a9d55c8d034fe483298185fd716b3b,
title = "Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy",
abstract = "The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.",
author = "Takahiko Nakagawa and Waichi Sato and Olena Glushakova and Marcelo Heinig and Tracy Clarke and Martha Campbell-Thompson and Yukio Yuzawa and Atkinson, {Mark A.} and Johnson, {Richard J.} and Byron Croker",
year = "2007",
month = "2",
day = "1",
doi = "10.1681/ASN.2006050459",
language = "English",
volume = "18",
pages = "539--550",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "2",

}

Nakagawa, T, Sato, W, Glushakova, O, Heinig, M, Clarke, T, Campbell-Thompson, M, Yuzawa, Y, Atkinson, MA, Johnson, RJ & Croker, B 2007, 'Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy', Journal of the American Society of Nephrology, vol. 18, no. 2, pp. 539-550. https://doi.org/10.1681/ASN.2006050459

Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. / Nakagawa, Takahiko; Sato, Waichi; Glushakova, Olena; Heinig, Marcelo; Clarke, Tracy; Campbell-Thompson, Martha; Yuzawa, Yukio; Atkinson, Mark A.; Johnson, Richard J.; Croker, Byron.

In: Journal of the American Society of Nephrology, Vol. 18, No. 2, 01.02.2007, p. 539-550.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy

AU - Nakagawa, Takahiko

AU - Sato, Waichi

AU - Glushakova, Olena

AU - Heinig, Marcelo

AU - Clarke, Tracy

AU - Campbell-Thompson, Martha

AU - Yuzawa, Yukio

AU - Atkinson, Mark A.

AU - Johnson, Richard J.

AU - Croker, Byron

PY - 2007/2/1

Y1 - 2007/2/1

N2 - The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.

AB - The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.

UR - http://www.scopus.com/inward/record.url?scp=33846701668&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846701668&partnerID=8YFLogxK

U2 - 10.1681/ASN.2006050459

DO - 10.1681/ASN.2006050459

M3 - Article

VL - 18

SP - 539

EP - 550

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 2

ER -