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. 2021 Jan 22;12:549. doi: 10.1038/s41467-020-20832-7

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 9 — Fetuin-A (Ahsg) is a HIF target gene that locally protects the kidney from hypoxia-induced renal damage and functional deterioration. It is implicated in the clearance of calcifying nanoparticles, mitigation of inflammation, attenuation of fibrotic tissue remodeling, and polarization of macrophages. (I) In normoxia, liver-derived fetuin-A (green) locally binds calcium in mineral particles (light gray), inhibits their maturation and accumulation (dark gray). Macrophages exhibit an M2 anti-inflammatory phenotype (M2 MΦ, blue). (II) The relatively low abundance of fetuin-A-free calcium biominerals (dark red) in normoxic conditions is not sufficient to elicit a noticeable inflammatory response. The majority of macrophages is M2 polarized, only a small fraction shows a M1 pro-inflammatory phenotype (M1 MΦ, magenta). (III) In hypoxia, increased tissue damage leads to calcium mineral overload and a polarization shift towards M1 MΦ. However, local induction of fetuin-A (yellow) augments the clearance of calcium biominerals and keeps the polarization of M1 MΦ in check, thus preventing inflammation and fibrotic remodeling. (IV) Fetuin-A deficiency in an hypoxic environment leads to an unbalanced accumulation of calcium biominerals and their unchecked maturation (orange), which overwhelms the intrinsic clearing capacity of the tissue. This further promotes the polarization of pro-inflammatory M1 MΦ, and culminates in inflammation (red) and fibrotic tissue remodeling.