Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors
Kai Schledzewski, … , Julia Kzhyshkowska, Sergij Goerdt
Kai Schledzewski, … , Julia Kzhyshkowska, Sergij Goerdt
Published January 10, 2011
Citation Information: J Clin Invest. 2011;121(2):703-714. https://doi.org/10.1172/JCI44740.
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Research Article Hepatology

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

Abstract

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.

Authors

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, Sergij Goerdt

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Figure 6

Differential impairment of hepatic blood clearance for stabilin ligands.

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Differential impairment of hepatic blood clearance for stabilin ligands....
(A and B) Plasma (A) and urine (B) HA levels of 3- and 6-month-old WT, Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice of C57BL/6 genetic background were measured by ELISA. Elevated levels of HA were detected exclusively in Stab2–/– and Stab1–/–Stab2–/– animals, but not in Stab1–/– mice. Data represent mean ± SEM for at least 5 mice per genotype. (C) Schematic presentation of the protein domain organization of stabilin-1 and stabilin-2 shows the fragments used in the yeast 2-hybrid screening (P9) and GST-pull down assays. Stabilin-1 F1-2, stabilin-1 F5-6, stabilin-1 F7, stabilin-1 P9, stabilin-1 cytoplasmic tail (C-term), and stabilin-2 F7 are indicated by bars. GST pull-down assay demonstrating that fasciclin domains of both stabilin-1 and stabilin-2 interact with in vitro–translated GDF-15. GDF-15 neither binds to GST alone (negative control) nor to the GST-fused cytoplasmic tail of stabilin-1. n = 3. (D) Quantification of stabilin-1– and stabilin-2–mediated uptake of Alexa Fluor 488–labeled GDF-15 using flow cytometry. n = 3. Data represent mean ± SEM for 3 independent experiments. (E) 5 μg of recombinant human GDF-15 was injected in the tail vein of WT, Stab1–/–, Stab2, and Stab1–/–Stab2–/– mice of Balb/c genetic background, and plasma levels of hGDF-15 were measured after 5 hours (n = 16, n = 3, n = 3, n = 12, respectively). Increased levels of hGDF-15 were exclusively observed in Stab1–/–Stab2–/– samples indicating impaired clearance of GDF-15 only upon combined absence of both stabilin receptors. Data represent mean ± SEM. *P < 0.05; **P < 0.01.