MXRA5 is a TGF-β1-regulated human protein with anti-inflammatory and anti-fibrotic properties.
Current therapy for chronic kidney disease (CKD) is unsatisfactory because of an insufficient understanding of its pathogenesis. Matrix remodelling-associated protein 5 (MXRA5, adlican) is a human protein of unknown function with high kidney tissue expression, not present in rodents. Given the increased expression of MXRA5 in injured tissues, including the kidneys, we have suggested that MXRA5 may modulate kidney injury. MXRA5 immunoreactivity was observed in tubular cells in human renal biopsies and in urine from CKD patients. We then explored factors regulating MXRA5 expression and MXRA5 function in cultured human proximal tubular epithelial cells and explored MXRA5 expression in kidney cancer cells and kidney tissue. The fibrogenic cytokine transforming growth factor-β1 (TGFβ1) up-regulated MXRA5 mRNA and protein expression. TGFβ1-induced MXRA5 up-regulation was prevented by either interference with TGFβ1 activation of the TGFβ receptor 1 (TGFBR1, ALK5) or by the vitamin D receptor agonist paricalcitol. By contrast, the pro-inflammatory cytokine TWEAK did not modulate MXRA5 expression. MXRA5 siRNA-induced down-regulation of constitutive MXRA5 expression resulted in higher TWEAK-induced expression of chemokines. In addition, MXRA5 down-regulation resulted in a magnified expression of genes encoding extracellular matrix proteins in response to TGFβ1. Furthermore, in clear cell renal cancer, von Hippel-Lindau (VHL) regulated MXRA5 expression. In conclusion, MXRA5 is a TGFβ1- and VHL-regulated protein and, for the first time, we identify MXRA5 functions as an anti-inflammatory and anti-fibrotic molecule. This information may yield clues to design novel therapeutic strategies in diseases characterized by inflammation and fibrosis.
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.
Jonay
J
Poveda
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.
Ana B
AB
Sanz
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.
Beatriz
B
Fernandez-Fernandez
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.
Susana
S
Carrasco
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.|School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain.
Marta
M
Ruiz-Ortega
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.
Pablo
P
Cannata-Ortiz
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.|School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain.|Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.
Alberto
A
Ortiz
IIS-Fundacion Jimenez Diaz Universidad Autonoma de Madrid, REDINREN, Madrid, Spain.
Maria D
MD
Sanchez-Niño
D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology; D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004872:Ergocalciferols; C575909:MXRA5 protein, human; D011509:Proteoglycans; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C084656:paricalcitol; D051794:Von Hippel-Lindau Tumor Suppressor Protein
adlican; chronic kidney disease; fibrosis; inflammation; kidney; perlecan; polycystic kidney disease