Adenovirus-mediated gene transfer of TGF-β1 to the renal glomeruli leads to proteinuria.
The mechanism of proteinuria in many common kidney diseases involves glomerular hemodynamic effects and local expression of angiogenic, fibrogenic, and vasoactive factors. Transforming growth factor (TGF)-β has been associated with many diseases involving proteinuria and renal fibrosis. TGF-β has been shown to induce podocyte dedifferentiation in vitro, but its in vivo effects on the glomerular filtration barrier are not well described. In this study, we used an adenovirus vector to transfer active TGF-β1 to the glomeruli of rat kidneys. Transient TGF-β1 overexpression induced significant proteinuria, podocyte foot process effacement, nephrin down-regulation, and nephrinuria. The expression of synaptopodin was also significantly down-regulated by TGF-β1. Increased glomerular expression of Snail, suggestive of an in vivo dedifferentiation process, was associated with a loss of podocyte epithelial markers. The expression of angiopoietin-1 and angiopoietin-2 was significantly increased in TGF-β1-transfected glomeruli, and TGF-β1 increased the expression of the angiopoietin receptor, Tie2, in podocyte cell culture. TGF-β1 down-regulated nephrin and synaptopodin expression in podocytes in cell culture; this effect was reversed by the blockade of both angiopoietin and Tie2 activities. These findings suggest that locally produced TGF-β1 can cause podocyte dedifferentiation marked by a loss of synaptopodin, nephrin, and foot process effacement, partly regulated by angiopoietins. This process represents a novel pathway that may explain proteinuria in a variety of common renal diseases.
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Ayesha
A
Ghayur
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Limin
L
Liu
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Martin
M
Kolb
Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
Arun
A
Chawla
Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
Shahid
S
Lambe
Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
Anil
A
Kapoor
Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: margetts@mcmaster.ca.
Peter J
PJ
Margetts
D000199:Actins / Q000378:metabolism; D000256:Adenoviridae; D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D054337:Cell Dedifferentiation; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D060730:Glomerular Filtration Barrier / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism / Q000652:urine; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000209:etiology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071250:Snail Family Transcription Factors; D016708:Synaptophysin / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000502:physiology*
D000199:Actins; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D008565:Membrane Proteins; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D016708:Synaptophysin; C504262:Synpr protein, rat; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C113267:nephrin