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, 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
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
View: Text | PDF
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

×

Figure 2

Liver phenotype of stabilin-deficient mice.

Options: View larger image (or click on image) Download as PowerPoint
Liver phenotype of stabilin-deficient mice. (A) Representative liver sec...
(A) Representative liver sections of 6-month-old WT, Stab1–/–, Stab2–/–, and Stab1–/–Stab2–/– mice of C57BL/6 genetic background were stained with Sirius red to identify the degree of fibrosis (n = 5). No Sirius red–positive fibers except around large blood vessels were detected in WT specimens, whereas few positive fibers were seen in Stab1–/– and Stab2–/– specimens. Sirius red staining of Stab1–/–Stab2–/– livers identified fibrotic fibers along the sinusoidal network. Original magnification, ×100. Scale bars: 100 μm. (B) Representative transmission EM images of liver sinusoids captured from 6-month-old WT as well as Stab1–/–Stab2–/– mice. Collagen fibers in the space of Disse close to the sinusoidal lumen are indicated by arrows. H, hepatocyte; SL, sinusoidal lumen. n = 3. Original magnification, ×10,000. Scale bar: 10 μm. (C) Activity levels of liver AST and ALT were measured in the plasma of 18-month-old C57BL/6 WT, C57BL/6 Stab1–/–, C57BL/6 Stab2–/–, and C57BL/6 Stab1–/–Stab2–/– mice. No statistically significant differences were found, indicating normal liver function even in very old Stab1–/–Stab2–/– animals. Data are mean ± SEM from 5 mice. (D) Activity levels of GLDH were measured in the plasma of C57BL/6 WT, C57BL/6 Stab1–/–, C57BL/6 Stab2–/–, and C57BL/6 Stab1–/–Stab2–/– mice of the indicated age as a marker of necrotic processes. A significant increase of GLDH was observed only in 18-month-old C57BL/6 animals. Data represent mean ± SEM from 5 mice. **P < 0.01 relative to Stab1–/–Stab2–/– values.