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 3

Kidney phenotype of stabilin-deficient mice.

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Kidney phenotype of stabilin-deficient mice. (A) Representative PAS-stai...
(A) Representative PAS-stained kidney sections from 3-month-old WT, Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice of Balb/c genetic background. The glomeruli from WT as well as Stab1–/– and Stab2–/– mice had a normal appearance. In contrast, mesangial expansion was evident in Stab1–/–Stab2–/– mice (arrows) (n = 3). Original magnification, ×400. Scale bars: 20 μm. (B) Representative kidney sections of 3-month-old WT and Stab1–/–Stab2–/– mice of C57BL/6 background were stained with Sirius red to identify the degree of fibrosis (n = 3). Strong Sirius red–positive staining indicating collagen deposition was detected only in Stab1–/–Stab2–/– glomeruli. The extent of the glomerulosclerosis was similar in Stab1–/–Stab2–/– mice of both Balb/c and C57BL/6 genetic background (not shown). Original magnification, ×200. Scale bars: 50 μm. (C) Representative transmission EM images of 4-week-old Stab1–/–Stab2–/– glomeruli of Balb/c genetic background as compared with WT showed large deposits of fibrillar material (red arrows) and a severely enlarged mesangium (M) with narrowing of capillary lumens (C), partial loss of foot processes (FP) and regular basement membrane (BM). n = 3. Original magnification, ×10,000. Scale bars: 10 μm. (D) Urine of 3- and 6-month-old Balb/c and 3-, 6-, and 18-month-old C57BL/6 mice of all genotypes was collected and analyzed for albumin content by competitive ELISA. Albumine levels were significantly increased in all Stab1–/–Stab2–/– samples in comparison with WT and single-deficient animals. Data represent mean ± SEM from 5 mice. **P < 0.01 relative to WT values.