Opposite role of CD44-standard and CD44-variant-3 in tubular injury and development of renal fibrosis during chronic obstructive nephropathy.
Chronic kidney diseases (CKDs) are characterized by tubular atrophy and interstitial fibrosis. We previously showed that in obstructive nephropathy de novo CD44 renal expression contributes to renal fibrosis but attenuates tubular damage/apoptosis. As CD44-standard (CD44s) has been linked to TGF-β1-mediated actions and CD44-variant-3 (CD44v3) favors HGF-c-Met binding, we compared the functional properties of these CD44 isoforms in the progression of obstructive nephropathy, using specific CD44-variant knockout/knockin mice. The presence of CD44v3 diminished tubular damage during obstructive nephropathy, decreased apoptosis, and increased proliferation of tubular epithelial cells, and prevented renal fibrosis development. In contrast, expression of CD44s led to increased tubular damage and tubular epithelial cell apoptosis, and more renal fibrosis. A relative increase in renal β-catenin expression, HGF production, and HGF/c-Met signaling, together with a relative inhibition of TGF-β1 downstream signaling and TGF-β type I receptor expression, was found in CD44v3 mice compared with CD44s littermates. In line with this, Wnt3a/HGF treatment of tubular cells resulted in higher β-catenin/p-AKT levels in CD44v3(+) tubular epithelial cells, whereas TGF-β1 induced a mild collagen I upregulation in CD44v3(+) mouse embryonic fibroblasts as compared with CD44s(+) cells. Thus, CD44s and CD44v3 exert opposite roles in the progression of obstructive nephropathy, with CD44v3-v10 being the protective isoform that delays evolution of the renal pathology.
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Elena
E
Rampanelli
Maastricht Radiation Oncology (Maastro), GROW School for Oncology and Developmental Biology, University of Maastricht, Maastricht, The Netherlands.
Kasper M A
KM
Rouschop
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Nike
N
Claessen
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Gwendoline J D
GJ
Teske
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Steven T
ST
Pals
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Jaklien C
JC
Leemans
1] Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands [2] Department of Pathology, Radboud University Nijmegen Center, Nijmegen, The Netherlands.
Sandrine
S
Florquin
D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism; D004847:Epithelial Cells; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000150:complications; D060509:Wnt3A Protein / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
D024042:Collagen Type I; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D060509:Wnt3A Protein; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077293:Receptor, Transforming Growth Factor-beta Type I