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

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 (FbIn7) is a matricellular protein structurally similar to elastogenic short fibulins, shown to bind dental mesenchymal cells and heparin. Here, we report that FbIn7 is highly expressed in renal tubular epithelium in the adult kidney and mediates renal calcification in mice. In vitro analysis revealed that FbIn7 bound heparin at the N-terminal coiled-coil domain. In Fbln7-expressing CHO-K1 cells, exogenous heparin increased the release of FbIn7 into conditioned media in a dose-dependent manner. This heparin-induced FbIn7 release was abrogated in CHO-745 cells lacking heparan sulfate proteoglycan or in CHO-K1 cells expressing the FbIn7 mutant lacking the N-terminal coiled-coil domain, suggesting that FbIn7 was tethered to pericellular matrix via this domain. Interestingly, FbIn7 knockout (FbIn7(-/-)) mice were protected from renal tubular calcification induced by high phosphate diet. Mechanistically, FbIn7 bound artificial calcium phosphate particles (aCPP) implicated in calcification and renal inflammation. Binding was decreased significantly in FbIn7(-/-) primary kidney cells relative to wild-type cells. Further, overexpression of FbIn7 increased binding to aCPP. Addition of heparin reduced binding between aCPP and wild-type cells to levels of FbIn7(-/-) cells. Taken together, our study suggests that FbIn7 is a local mediator of calcium deposition and that releasing FbIn7 from the cell surface by heparin/heparin derivatives or FbIn7 inhibitory antibodies may provide a novel strategy to prevent ectopic calcification in vivo. (C) 2018 Elsevier B.V. All rights reserved.