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Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors

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Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endotheli...

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Main Authors: Schledzewski, Kai (Author) , Géraud, Cyrill (Author) , Arnold, Bernd (Author) , Wang, Shijun (Author) , Gröne, Hermann-Josef (Author) , Kempf, Tibor (Author) , Wollert, Kai Christoph (Author) , Straub, Beate Katharina (Author) , Schirmacher, Peter (Author) , Demory, Alexandra (Author) , Schönhaber, Hiltrud (Author) , Gratchev, Alexei (Author) , Dietz, Lisa (Author) , Thierse, Hermann-Josef (Author) , Kzhyshkowska, Julia (Author) , Goerdt, Sergij (Author)
Format: Article (Journal)
Language:English
Published: January 10, 2011
In: The journal of clinical investigation
Year: 2011, Volume: 121, Issue: 2, Pages: 703-714
ISSN:1558-8238
DOI:10.1172/JCI44740
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Author Notes:Kai Schledzewski, Cyrill Géraud, Bernd Arnold, Shijun Wang, Hermann-Josef Gröne, Tibor Kempf, Kai C. Wollert, Beate K. Straub, Peter Schirmacher, Alexandra Demory, Hiltrud Schönhaber, Alexei Gratchev, Lisa Dietz, Hermann-Josef Thierse, Julia Kzhyshkowska, and Sergij Goerdt
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Summary:Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endothelial cells (LSEC). Besides the mannose receptor, stabilin-1 and stabilin-2 are the major scavenger receptors expressed by LSEC. To more clearly elucidate the functions of stabilin-1 and -2, we have generated mice lacking stabilin-1, stabilin-2, or both stabilin-1 and -2 (Stab1–/–Stab2–/– mice). Mice lacking either stabilin-1 or stabilin-2 were phenotypically normal; however, Stab1–/–Stab2–/– mice exhibited premature mortality and developed severe glomerular fibrosis, while the liver showed only mild perisinusoidal fibrosis without dysfunction. Upon kidney transplantation into WT mice, progression of glomerular fibrosis was halted, indicating the presence of profibrotic factors in the circulation of Stab1–/–Stab2–/– mice. While plasma levels of known profibrotic cytokines were unaltered, clearance of the TGF-β family member growth differentiation factor 15 (GDF-15) was markedly impaired in Stab1–/–Stab2–/– mice but not in either Stab1–/– or Stab2–/– mice, indicating that it is a common ligand of both stabilin-1 and stabilin-2. These data lead us to conclude that stabilin-1 and -2 together guarantee proper hepatic clearance of potentially noxious agents in the blood and maintain tissue homeostasis not only in the liver but also distant organs.
Item Description:Gesehen am 12.10.2022
Physical Description:Online Resource
ISSN:1558-8238
DOI:10.1172/JCI44740

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