Fibulin-7, a heparin binding matricellular protein, promotes renal tubular calcification in mice

Jun Tsunezumi, Hidekazu Sugiura, Lalhaba Oinam, Aktar Ali, Bui Quoc Thang, Aiko Sada, Yoshito Yamashiro, Makoto Kuro-O, Hiromi Yanagisawa

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Ectopic calcification occurs during development of chronic kidney disease and has a negative impact on long-term prognosis. The precise molecular mechanism and prevention strategies, however, are not established. Fibulin-7 (Fbln7) is a matricellular protein structurally similar to elastogenic short fibulins, shown to bind dental mesenchymal cells and heparin. Here, we report that Fbln7 is highly expressed in renal tubular epithelium in the adult kidney and mediates renal calcification in mice. In vitro analysis revealed that Fbln7 bound heparin at the N-terminal coiled-coil domain. In Fbln7-expressing CHO-K1 cells, exogenous heparin increased the release of Fbln7 into conditioned media in a dose-dependent manner. This heparin-induced Fbln7 release was abrogated in CHO-745 cells lacking heparan sulfate proteoglycan or in CHO-K1 cells expressing the Fbln7 mutant lacking the N-terminal coiled-coil domain, suggesting that Fbln7 was tethered to pericellular matrix via this domain. Interestingly, Fbln7 knockout (Fbln7−/−) mice were protected from renal tubular calcification induced by high phosphate diet. Mechanistically, Fbln7 bound artificial calcium phosphate particles (aCPP) implicated in calcification and renal inflammation. Binding was decreased significantly in Fbln7−/− primary kidney cells relative to wild-type cells. Further, overexpression of Fbln7 increased binding to aCPP. Addition of heparin reduced binding between aCPP and wild-type cells to levels of Fbln7−/− cells. Taken together, our study suggests that Fbln7 is a local mediator of calcium deposition and that releasing Fbln7 from the cell surface by heparin/heparin derivatives or Fbln7 inhibitory antibodies may provide a novel strategy to prevent ectopic calcification in vivo.

Original languageEnglish (US)
JournalMatrix Biology
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • Calcification
  • Elastogenesis
  • Fibulin
  • Kidney
  • Pericellualr matrix

ASJC Scopus subject areas

  • Molecular Biology

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    Tsunezumi, J., Sugiura, H., Oinam, L., Ali, A., Thang, B. Q., Sada, A., Yamashiro, Y., Kuro-O, M., & Yanagisawa, H. (Accepted/In press). Fibulin-7, a heparin binding matricellular protein, promotes renal tubular calcification in mice. Matrix Biology. https://doi.org/10.1016/j.matbio.2018.04.014