Renal tubular angiogenic dysregulation in anti-Thy1.1 glomerulonephritis.
Peritubular vascular changes and hypoxia after glomerular injury may explain subsequent tubulointerstitial injury and fibrosis. Several studies suggested that the expected tubulointerstitial angiogenic response is actively suppressed in this setting. The mechanism of this aberrant response has not been clearly identified. We used a common model of glomerular injury in rats to assess vascular changes and to identify potential factors associated with this aberrant response. Anti-Thy1.1 antibody administration (1 or 4 weekly doses) led to a dose-dependent renal damage characterized by elevated urea and tubulointerstitial fibrosis as assessed by Picro-Sirius Red staining. We quantified peritubular capillaries using CD31 and CD34 immunohistochemistry and showed that tubular angiogenic dysregulation was associated with peritubular capillary rarefaction. Using laser capture microdissection, we demonstrated an early induction of fibrogenic and angiogenic factors in the glomeruli and a subsequent dysregulated angiogenic response in the tubulointerstitial compartment. Proximal tubules of anti-Thy1.1-treated animals had increased pigment epithelial-derived factor (PEDF) expression by immunohistochemistry. Protein taken by laser capture microdissection also showed that PEDF was upregulated. Temporally associated with PEDF expression was a transient downregulation of tubular hypoxia-inducible factor (HIF)1α. In a human proximal tubular cell culture, we show that PEDF downregulates HIF1α protein and gene expression in cells exposed to 1% oxygen. In anti-Thy1.1 glomerulonephritis, there is aberrent tubular angiogenesis associated with glomerular injury and tubulointersititial fibrosis. We showed that PEDF may be involved by downregulating HIF1α. Further work is needed to elucidate the mechanism of PEDF upregulation and action in the tubules.
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Davide P
DP
Cina
Hui
H
Xu
Limin
L
Liu
Laszlo
L
Farkas
Daniela
D
Farkas
Martin
M
Kolb
Peter J
PJ
Margetts
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis / Q000276:immunology; D002460:Cell Line; D015536:Down-Regulation; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D005921:Glomerulonephritis / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009414:Nerve Growth Factors / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000378:metabolism; D018800:Thy-1 Antigens / Q000276:immunology; D015854:Up-Regulation; D014508:Urea / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D018952:Antigens, CD34; D005136:Eye Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009414:Nerve Growth Factors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015843:Serpins; D018800:Thy-1 Antigens; D014508:Urea; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C497444:Hif1a protein, rat