Open AccessCD44 Disruption Prevents Degeneration of the Capillary Network in Obstructive Nephropathy via Reduction of TGF-β1–Induced Apoptosis
Author(s) -
Kasper M.A. Rouschop,
Nike Claessen,
Steven T. Pals,
Jan J. Weening,
Sandrine Florquin
Publication year - 2006
Publication title -
journal of the american society of nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1681/asn.2005080808
Subject(s) - cd44 , fibrosis , cancer research , hyaluronic acid , endothelial stem cell , chemistry , medicine , endocrinology , microbiology and biotechnology , biology , cell , anatomy , biochemistry , in vitro
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.