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CD44 Deficiency Increases Tubular Damage But Reduces Renal Fibrosis in Obstructive Nephropathy

Kasper M.A. Rouschop^*, Miguel E. Sewnath, Nike Claessen^*, Joris J.T.H. Roelofs^*, Inge Hoedemaeker^*, Ronald van der Neut^*, Jan Aten^*, Steven T. Pals^*, Jan J. Weening^* and Sandrine Florquin^*

Departments of *Pathology and Surgery, Academic Medical Center, Amsterdam, The Netherlands.

Correspondence to Dr. Kasper Rouschop, Department of Pathology, Academic Medical Center, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands. Phone: +31-20-5665653; Fax: 31-20-6960389; E-mail: k.m.rouschop{at}amc.uva.nl

ABSTRACT. CD44 is a glycoprotein involved in inflammation and cell-cell/cell-matrix interactions. CD44 is upregulated in the kidney upon injury; however, its role in the pathogenesis of renal damage and fibrosis remains largely unknown. The authors show that mice lacking CD44 developed more tubular damage, associated with decreased proliferation and increased apoptosis of tubular epithelial cells, but less renal fibrosis after unilateral ureteral obstruction. In addition, impaired influx of macrophages and decreased accumulation of myofibroblasts was observed in the obstructed kidney of CD44^-/- mice compared with CD44^+/+ mice. Hepatocyte growth factor (HGF) and transforming growth factor-1 (TGF-1) exert reciprocal functions in the progression of renal diseases and interact with CD44 in vitro. For the first time, the authors establish diminished HGF-signaling, via its high affinity receptor c-Met, in the absence of CD44 in vivo. In parallel, the signaling of TGF-1 reflected by the relative phosphorylation and nuclear translocation of Smad-2 and Smad-3 was reduced in the obstructed kidney of CD44^-/- mice. In conclusion, CD44 exerts protective effects on tubuli but contributes to renal fibrogenesis at least in part through enhancement of HGF and TGF-1 signaling pathway in obstructive nephropathy.

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