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 5

Effect of circulating factors on kidney phenotype.

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Effect of circulating factors on kidney phenotype. (A) Representative PA...
(A) Representative PAS-stained sections of kidneys from 7-week-old (lower left) and 15-week-old (upper right) Stab1–/–Stab2–/– mice and of Stab1–/–Stab2–/––to–WT (lower right) as well as WT-to-WT (upper left) kidney transplants at 56 days after transplantation are shown (n = 3). While WT control transplants (Tx) were unaffected and Stab1–/–Stab2–/– glomeruli of 15-week-old animals displayed progression of glomerular fibrosis, glomeruli of Stab1–/–Stab2–/––to–WT renal transplants showed regression of fibrosis after transplantation. Original magnification, ×400. (B) Quantitative evaluation of glomerular fibrosis in Stab1–/–Stab2–/––to–WT renal transplants after transplantation (n = 3) showed a statistically significant decrease in mesangial area (P = 0.0282) as compared with 15-week-old Stab1–/–Stab2–/– kidneys, while comparison with 7-week-old Stab1–/–Stab2–/– kidneys showed a tendency toward reduction of mesangial area. (C and D) Plasma samples of 3-, 6-, and 12-month-old WT, Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice of C57BL/6 genetic background were analyzed for P I NP and P III N) by ELISA. As only stabilin-2, but not stabilin-1, is a scavenger receptor for these propeptides, elevated levels of the propeptides found only in Stab1–/–Stab2–/– animals indicate increased de novo synthesis of collagens in Stab1–/–Stab2–/– mice. (E and F) Plasma samples of 3- and 12-month-old WT, Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice (C57BL/6 background) were measured for TGF-β1 (E) and PDFG-B (F) by ELISA. No elevated levels of known profibrotic cytokines were detected in the tested stabilin animals Data represent mean ± SEM for at least 5 mice per genotype. **P < 0.01.