Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF

Youli Wang, Kathleen O. Heilig, Andrew W. Minto, Shenglin Chen, Minghui Xiang, David A. Dean, Richard C. Geiger, Anthony Chang, Dimitrina D. Pravtcheva, Martin Schlimme, Dilip K. Deb, Ying Wang, Charles W. Heilig

Research output: Contribution to journalArticle

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Abstract

Reduced nephron numbers may predispose to renal failure. We hypothesized that glucose transporters (GLUTs) may contribute to progression of the renal disease, as GLUTs have been implicated in diabetic glomerulosclerosis and hypertensive renal disease with mesangial cell (MC) stretch. The Os (oligosyndactyly) allele that typically reduces nephron number by 50%, was repeatedly backcrossed from ROP (Ra/ (ragged), Os/ (oligosyndactyly), and Pt/ (pintail)) Os/ mice more than six times into the Fvb mouse background to obtain Os/ and / mice with the Fvb background for study. Glomerular function, GLUT1, signaling, albumin excretion, and structural and ultrastructural changes were assessed. The FvbROP Os/ mice (Fvb background) exhibited increased glomerular GLUT1, glucose uptake, VEGF, glomerular hypertrophy, hyperfiltration, extensive podocyte foot process effacement, marked albuminuria, severe extracellular matrix (ECM) protein deposition, and rapidly progressive renal failure leading to their early demise. Glomerular GLUT1 was increased 2.7-fold in the FvbROP Os/ mice vs controls at 4 weeks of age, and glucose uptake was increased 2.7-fold. These changes were associated with the activation of glomerular PKCΒ1 and NF-B p50 which contribute to ECM accumulation. The cyclic mechanical stretch of MCs in vitro, used as a model for increased MC stretch in vivo, reproduced increased GLUT1 at 48 h, a stimulus for increased VEGF expression which followed at 72 h. VEGF was also shown to act in a positive feedback manner on MC GLUT1, increasing GLUT1 expression, glucose uptake and fibronectin (FN) accumulation in vitro, whereas antisense suppression of GLUT1 largely blocked FN upregulation by VEGF. The FvbROP Os/ mice exhibited an early increase in glomerular GLUT1 leading to increased glomerular glucose uptake PKCΒ1, and NF-B activation, with excess ECM accumulation. A GLUT1-VEGF-GLUT1 positive feedback loop may play a key role in contributing to renal disease in this model of nondiabetic glomerulosclerosis.

Original languageEnglish (US)
Pages (from-to)83-97
Number of pages15
JournalLaboratory Investigation
Volume90
Issue number1
DOIs
StatePublished - Jan 1 2010

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Albuminuria
Nephrons
Vascular Endothelial Growth Factor A
Renal Insufficiency
Mesangial Cells
Glucose
Facilitative Glucose Transport Proteins
Kidney
Fibronectins
Extracellular Matrix
Podocytes
Extracellular Matrix Proteins
Diabetic Nephropathies
Hypertrophy
Disease Progression
Albumins
Up-Regulation
Alleles

Keywords

  • FVB mouse
  • GLUT1
  • Glucose transporter
  • Oligosyndactyly
  • Renal failure
  • VEGF

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF. / Wang, Youli; Heilig, Kathleen O.; Minto, Andrew W.; Chen, Shenglin; Xiang, Minghui; Dean, David A.; Geiger, Richard C.; Chang, Anthony; Pravtcheva, Dimitrina D.; Schlimme, Martin; Deb, Dilip K.; Wang, Ying; Heilig, Charles W.

In: Laboratory Investigation, Vol. 90, No. 1, 01.01.2010, p. 83-97.

Research output: Contribution to journalArticle

Wang, Y, Heilig, KO, Minto, AW, Chen, S, Xiang, M, Dean, DA, Geiger, RC, Chang, A, Pravtcheva, DD, Schlimme, M, Deb, DK, Wang, Y & Heilig, CW 2010, 'Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF', Laboratory Investigation, vol. 90, no. 1, pp. 83-97. https://doi.org/10.1038/labinvest.2009.95
Wang, Youli ; Heilig, Kathleen O. ; Minto, Andrew W. ; Chen, Shenglin ; Xiang, Minghui ; Dean, David A. ; Geiger, Richard C. ; Chang, Anthony ; Pravtcheva, Dimitrina D. ; Schlimme, Martin ; Deb, Dilip K. ; Wang, Ying ; Heilig, Charles W. / Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF. In: Laboratory Investigation. 2010 ; Vol. 90, No. 1. pp. 83-97.
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abstract = "Reduced nephron numbers may predispose to renal failure. We hypothesized that glucose transporters (GLUTs) may contribute to progression of the renal disease, as GLUTs have been implicated in diabetic glomerulosclerosis and hypertensive renal disease with mesangial cell (MC) stretch. The Os (oligosyndactyly) allele that typically reduces nephron number by 50{\%}, was repeatedly backcrossed from ROP (Ra/ (ragged), Os/ (oligosyndactyly), and Pt/ (pintail)) Os/ mice more than six times into the Fvb mouse background to obtain Os/ and / mice with the Fvb background for study. Glomerular function, GLUT1, signaling, albumin excretion, and structural and ultrastructural changes were assessed. The FvbROP Os/ mice (Fvb background) exhibited increased glomerular GLUT1, glucose uptake, VEGF, glomerular hypertrophy, hyperfiltration, extensive podocyte foot process effacement, marked albuminuria, severe extracellular matrix (ECM) protein deposition, and rapidly progressive renal failure leading to their early demise. Glomerular GLUT1 was increased 2.7-fold in the FvbROP Os/ mice vs controls at 4 weeks of age, and glucose uptake was increased 2.7-fold. These changes were associated with the activation of glomerular PKCΒ1 and NF-B p50 which contribute to ECM accumulation. The cyclic mechanical stretch of MCs in vitro, used as a model for increased MC stretch in vivo, reproduced increased GLUT1 at 48 h, a stimulus for increased VEGF expression which followed at 72 h. VEGF was also shown to act in a positive feedback manner on MC GLUT1, increasing GLUT1 expression, glucose uptake and fibronectin (FN) accumulation in vitro, whereas antisense suppression of GLUT1 largely blocked FN upregulation by VEGF. The FvbROP Os/ mice exhibited an early increase in glomerular GLUT1 leading to increased glomerular glucose uptake PKCΒ1, and NF-B activation, with excess ECM accumulation. A GLUT1-VEGF-GLUT1 positive feedback loop may play a key role in contributing to renal disease in this model of nondiabetic glomerulosclerosis.",
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AU - Heilig, Kathleen O.

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AU - Xiang, Minghui

AU - Dean, David A.

AU - Geiger, Richard C.

AU - Chang, Anthony

AU - Pravtcheva, Dimitrina D.

AU - Schlimme, Martin

AU - Deb, Dilip K.

AU - Wang, Ying

AU - Heilig, Charles W.

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N2 - Reduced nephron numbers may predispose to renal failure. We hypothesized that glucose transporters (GLUTs) may contribute to progression of the renal disease, as GLUTs have been implicated in diabetic glomerulosclerosis and hypertensive renal disease with mesangial cell (MC) stretch. The Os (oligosyndactyly) allele that typically reduces nephron number by 50%, was repeatedly backcrossed from ROP (Ra/ (ragged), Os/ (oligosyndactyly), and Pt/ (pintail)) Os/ mice more than six times into the Fvb mouse background to obtain Os/ and / mice with the Fvb background for study. Glomerular function, GLUT1, signaling, albumin excretion, and structural and ultrastructural changes were assessed. The FvbROP Os/ mice (Fvb background) exhibited increased glomerular GLUT1, glucose uptake, VEGF, glomerular hypertrophy, hyperfiltration, extensive podocyte foot process effacement, marked albuminuria, severe extracellular matrix (ECM) protein deposition, and rapidly progressive renal failure leading to their early demise. Glomerular GLUT1 was increased 2.7-fold in the FvbROP Os/ mice vs controls at 4 weeks of age, and glucose uptake was increased 2.7-fold. These changes were associated with the activation of glomerular PKCΒ1 and NF-B p50 which contribute to ECM accumulation. The cyclic mechanical stretch of MCs in vitro, used as a model for increased MC stretch in vivo, reproduced increased GLUT1 at 48 h, a stimulus for increased VEGF expression which followed at 72 h. VEGF was also shown to act in a positive feedback manner on MC GLUT1, increasing GLUT1 expression, glucose uptake and fibronectin (FN) accumulation in vitro, whereas antisense suppression of GLUT1 largely blocked FN upregulation by VEGF. The FvbROP Os/ mice exhibited an early increase in glomerular GLUT1 leading to increased glomerular glucose uptake PKCΒ1, and NF-B activation, with excess ECM accumulation. A GLUT1-VEGF-GLUT1 positive feedback loop may play a key role in contributing to renal disease in this model of nondiabetic glomerulosclerosis.

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