Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 21, Issue 1, Pages 154-164Publisher
WILEY
DOI: 10.1111/jcmm.12953
Keywords
chronic kidney disease; fibrosis; kidney; inflammation; polycystic kidney disease; perlecan; adlican
Categories
Funding
- Instituto de Salud Carlos III (FEDER funds, ISCIII RETIC REDINREN) [RD12/0021, PI13/00047, PI15/00298, PIE13/00051]
- Comunidad de Madrid [CIFRA S2010/BMD-2378]
- Sociedad Espanola de Nefrologia. Programa Intensificacion Actividad Investigadora (ISCIII/Agencia Lain-Entralgo/CM)
- ISCIII [JR14/00028, MS12/03262, MS14/00133, IIS-FJD PT13/0010/0012]
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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-1 (TGF1) up-regulated MXRA5 mRNA and protein expression. TGF1-induced MXRA5 up-regulation was prevented by either interference with TGF1 activation of the TGF 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 TGF1. Furthermore, in clear cell renal cancer, von Hippel-Lindau (VHL) regulated MXRA5 expression. In conclusion, MXRA5 is a TGF1- 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.
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