RGD Reference Report - Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF. - Rat Genome Database

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

Authors: 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 
Citation: Wang Y, etal., Lab Invest. 2010 Jan;90(1):83-97. doi: 10.1038/labinvest.2009.95. Epub 2009 Nov 16.
RGD ID: 12879501
Pubmed: PMID:19918242   (View Abstract at PubMed)
PMCID: PMC4150870   (View Article at PubMed Central)
DOI: DOI:10.1038/labinvest.2009.95   (Journal Full-text)

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 approximately 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 PKCbeta1 and NF-kappaB 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 PKCbeta1, and NF-kappaB 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
glomerulosclerosis  ISOSlc2a1 (Mus musculus)12879501; 12879501 RGD 
glomerulosclerosis  IEP 12879501 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to mechanical stimulus  IEP 12879501 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc2a1  (solute carrier family 2 member 1)

Genes (Mus musculus)
Slc2a1  (solute carrier family 2 (facilitated glucose transporter), member 1)

Genes (Homo sapiens)
SLC2A1  (solute carrier family 2 member 1)


Additional Information