CD44-splice variant 3 attenuates tubular injury in the early stage of chronic obstructive nephropathy and reduces the pro-fibrotic effects of TGF- β1

Renal tubule-interstitial fibrosis is the end result of chronic inflammation and it is regulated by a complex network of cytokines, including the pro-fibrotic factor TGF-β1 and the two anti-fibrotic cytokines BMP-7 and HGF. One of the molecules that might orchestrate the balance between TGF-β1 and HGF/BMP-7 is CD44, which is a surface glycoprotein involved in inflammation and cell-cell/cell-matrix interactions. All CD44 isoforms have a hyaluronan-binding site but differ in the length of extracellular chain and are therefore interacting with distinct molecules: the CD44 standard (CD44s) isoform can facilitate TGF-β1 signalling upon binding to hyaluronan, while the CD44-variant 3 (CD44v3) is capable of interacting with heparin-binding growth factors (HGF, BMP-7) due to its attached heparan sulfate moieties.
To study the role of CD44 isoforms expression on tubular injured cells, we compared the progression of unilateral obstructive nephropathy (UUO) in wild-type mice, and transgenic mice overexpressing either CD44s or CD44v3 specifically on proximal tubular epithelial cells (TEC) and we performed in vitro stimulation of primary TEC.

In early stage of chronic obstructive nephropathy, transgenic mice overexpressing CD44v3 on TEC display less tubular damage and myofibroblasts accumulation together with diminished TGF-β1 intracellular pathway activation and increased BMP-7 signalling. In vitro stimulations of primary TEC suggest that the CD44v3 isoform renders the cells less susceptible to the TGFβ1 actions; indeed, CD44v3-TECs synthesize less α-SMA, CTGF, TGF-β1 and collagen type1 mRNAs then the Wt-, and CD44s-TECs through a decreased TGF-β1 signalling activation.

Currently, we are focusing on the in vitro study of the effects of HGF and BMP-7 on primary TEC in order to elucidate the in vivo data, as the CD44v3-obstructed kidneys showed increased BMP-7 signalling and equal level of HGF signalling activation besides lower levels of HGF production in respect to Wt- and CD44s-obstructed kidneys.

No relevant conflicts of interest declared.