Format

Send to

Choose Destination
Matrix Biol. 2018 Dec;74:5-20. doi: 10.1016/j.matbio.2018.04.014. Epub 2018 May 3.

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

Author information

1
Department of Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
2
Fourth Department of Internal Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan; Department of Nephrology, Division of Medicine, Saiseikai Kurihashi Hospital, Saitama 349-1105, Japan.
3
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 305-8577, Japan.
4
Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
5
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; Department of Cardiovascular Surgery, University of Tsukuba, Tsukuba 305-8575, Japan.
6
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan.
7
Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
8
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan. Electronic address: hkyanagisawa@tara.tsukuba.ac.jp.

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.

KEYWORDS:

Calcification; Elastogenesis; Fibulin; Kidney; Pericellualr matrix

PMID:
29730503
DOI:
10.1016/j.matbio.2018.04.014
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center