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 1

Generation of Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice.

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Generation of Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice. (A) Rep...
(A) Representative liver sections of 3-month-old WT, Stab1–/– (stab-1), Stab2–/– (stab-2), and Stab1–/–Stab2–/– (stab-dko) mice of C57BL/6 genetic background were stained by immunohistochemistry with antibodies against stabilin-1 (upper row) and stabilin-2 (lower row). WT sections show sinusoidal distribution of both stabilins. No stabilin-1 was detected in Stab1–/–, no stabilin-2 was detected in Stab2–/–, and neither of the stabilins were expressed in Stab1–/–Stab2–/– animals. Original magnification, ×200. Scale bars: 50 μm. (B) Survival of WT, Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice (C57BL/6 background) over a period of 820 days (n = 38, n = 45, n = 43, and n = 40, respectively). Mean survival of Stab1–/–Stab2–/– mice was significantly (P < 0.001) reduced (415 d), if compared with WT (803 d), Stab1–/– (615 d), and Stab2–/– (625 d) strains. Single-deficient mice displayed a tendency toward reduced lifespan (Stab1–/– [P = 0.13] and Stab2–/– [P = 0.12]). (C) Survival of WT, Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice of Balb/c genetic background over a period of 751 days (n = 31, n = 44, n = 30, and n = 102, respectively). Mean survival of Stab1–/–Stab2–/– mice was dramatically reduced (269 d), if compared with WT (739 d), Stab1–/– (584 d), and Stab2–/– (618 d). Single-deficient mice displayed a tendency toward a reduced lifespan (Stab1–/– [P = 0.28]) and Stab2–/– [P = 0.06]) that did not reach the level of confidence (P < 0.05). (B and C) The survival data were analyzed by log-rank statistics, and pair-wise multiple comparison procedures were done by the Holm-Sidak method.