CD44 disruption prevents degeneration of the capillary network in obstructive nephropathy via reduction of TGF-beta1-induced apoptosis.
CD44 is a glycoprotein that is involved in inflammation and cell-cell/cell-matrix interactions, is upregulated in the kidney upon injury, and leads to fibrosis through enhancement of TGF-beta1 signaling. Absence of CD44 prevents development of renal fibrosis in unilateral ureteral obstruction (UUO). A hallmark of development of renal fibrosis is the degeneration of the capillary network. This study shows that CD44 is upregulated on capillary endothelial cells during UUO. For elucidation of the role of CD44 on peritubular endothelial cells in UUO, capillary network degeneration was compared in CD44+/+ and CD44-/- mice. As expected, degeneration of the capillary network was observed in CD44+/+ mice during UUO, associated with increased endothelial apoptosis. However, in the absence of CD44, degeneration of the network is prevented as a result of a decrease in the rate of apoptosis in endothelial cells. The divergence in endothelial apoptosis is not correlated to differential vascular endothelial growth factor or thrombospondin-1 expression. For further investigation of capillary regression, CD44+/+ and CD44-/- peritubular capillary endothelial cell lines were established. With the use of these cells, it is shown that interaction between CD44 and its ligand hyaluronic acid enhances the proapoptotic effect of TGF-beta1 but not thrombospondin-1 on endothelial cells, contributing to the degeneration of the capillary network. Blocking interaction between hyaluronic acid and CD44 therefore may be a potential therapeutic opportunity to preserve the capillary network and prevent the development of fibrosis in chronic renal disease.
Rouschop
Kasper M A
KM
Department of Pathology, Academic Medical Center, Room M2-108, PO Box 22668, 1100 DD Amsterdam, The Netherlands.
Claessen
Nike
N
Pals
Steven T
ST
Weening
Jan J
JJ
Florquin
Sandrine
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002196:Capillaries; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000276:immunology / Q000473:pathology*; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction / Q000276:immunology / Q000473:pathology
D018960:Hyaluronan Receptors; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1