Background: ICR-derived glomerulonephritis (ICGN) strain is a novel inbred strain of mice with a hereditary nephrotic syndrome. Deletion mutation of tensin 2 (Tns2), a focal adhesion molecule, has been suggested to be responsible for nephrotic syndrome in ICGN mice; however, the existence of other associative factors has been suggested. Methods and Results: To identify additional associative factors and to better understand the onset mechanism of nephrotic syndrome in ICGN mice, we conducted a comprehensive gene expression analysis using DNA microarray. Immune-related pathways were markedly altered in ICGN mice kidney as compared with ICR mice. Furthermore, the gene expression level of complement component 1, s subcomponent (C1s), whose human homologue has been reported to associate with lupus nephritis, was markedly low in ICGN mouse kidney. Real-time quantitative reverse transcription-polymerase chain reaction confirmed a low expression level of C1s in ICGN mouse liver where the C1s protein is mainly synthesized. A high serum level of anti-dsDNA antibody and deposits of immune complexes were also detected in ICGN mice by enzyme-linked immunosorbent assay and immunohistochemical analyses, respectively. Conclusion: Our results suggest that the immune system, especially the complement system, is associated with nephrotic syndrome in ICGN mice. We identified a low expression level of C1s gene as an additional associative factor for nephrotic syndrome in ICGN mice. Further studies are needed to elucidate the role of the complement system in the onset of nephrotic syndrome in ICGN mice.

1.
Ogura A, Asano T, Matsuda J, Noguchi Y, Yamamoto Y, Takano K, Nakagawa M: Development of nephrotic ICGN mice - the origin, reproductive ability, and incidence of glomerulonephritis. Jikken Dobutsu 1989;38:349-352.
[PubMed]
2.
Ogura A, Asano T, Matsuda J, Takano K, Nakagawa M, Fukui M: Characteristics of mutant mice (ICGN) with spontaneous renal lesions: a new model for human nephrotic syndrome. Lab Anim 1989;23:169-174.
[PubMed]
3.
Ogura A, Asano T, Suzuki O, Yamamoto Y, Noguchi Y, Kawaguchi H, Yamaguchi Y: Hereditary nephrotic syndrome with progression to renal failure in a mouse model (ICGN strain): clinical study. Nephron 1994;68:239-244.
[PubMed]
4.
Ogura A, Asano T, Matsuda J, Fujimura H: Evolution of glomerular lesions in nephrotic ICGN mice: serial biopsy study with electron microscopy. J Vet Med Sci 1991;53:513-515.
[PubMed]
5.
Ogura A, Asano T, Matsuda J, Koura M, Nakagawa M, Kawaguchi H, Yamaguchi Y: An electron microscopic study of glomerular lesions in hereditary nephrotic mice (ICGN strain). Virchows Arch A Pathol Anat Histopathol 1990;417:223-228.
[PubMed]
6.
Ogura A, Fujimura H, Asano T, Koura M, Naito I, Kobayashi Y: Early ultrastructural glomerular alterations in neonatal nephrotic mice (ICGN strain). Vet Pathol 1995;32:321-323.
[PubMed]
7.
Okamoto M, Yokoi N, Seriklawa T, Tajima M, Kurosawa T: Linkage mapping of the mouse nephrosis (nep) gene to chromosome 15. J Vet Med Sci 2001;63:1347-1350.
[PubMed]
8.
Cho AR, Uchio-Yamada K, Torigai T, Miyamoto T, Miyoshi I, Matsuda J, Kurosawa T, Kon Y, Asano A, Sasaki N, Agui T: Deficiency of the tensin2 gene in the ICGN mouse: an animal model for congenital nephrotic syndrome. Mamm Genome 2006;17:407-416.
[PubMed]
9.
Weigt C, Gaertner A, Wegner A, Korte H, Meyer HE: Occurrence of an actin-inserting domain in tensin. J Mol Biol 1992;227:593-595.
[PubMed]
10.
Nishino T, Sasaki N, Nagasaki K, Ahmad Z, Agui T: Genetic background strongly influences the severity of glomerulosclerosis in mice. J Vet Med Sci 2010;72:1313-1318.
[PubMed]
11.
Nishino T, Sasaki N, Nagasaki K, Ichii O, Kon Y, Agui T: The 129 genetic background affects susceptibility to glomerulosclerosis in tensin2-deficient mice. Biomed Res 2012;33:53-56.
[PubMed]
12.
Tamura K, Ono A, Miyagishima T, Nagao T, Urushidani T: Comparison of gene expression profiles among papilla, medulla and cortex in rat kidney. J Toxicol Sci 2006;31:449-469.
[PubMed]
13.
Amano MT, Ferriani VP, Florido MP, Reis ES, Delcolli MI, Azzolini AE, Assis-Pandochi AI, Sjoholm AG, Farah CS, Jensenius JC, Isaac L: Genetic analysis of complement c1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal c1s gene. Mol Immunol 2008;45:1693-1702.
[PubMed]
14.
Bienaime F, Quartier P, Dragon-Durey MA, Fremeaux-Bacchi V, Bader-Meunier B, Patey N, Salomon R, Noel LH: Lupus nephritis associated with complete c1s deficiency efficiently treated with rituximab: a case report. Arthritis Care Res (Hoboken) 2010;62:1346-1350.
[PubMed]
15.
Dragon-Durey MA, Quartier P, Fremeaux-Bacchi V, Blouin J, de Barace C, Prieur AM, Weiss L, Fridman WH: Molecular basis of a selective c1s deficiency associated with early onset multiple autoimmune diseases. J Immunol 2001;166:7612-7616.
[PubMed]
16.
Inoue N, Saito T, Masuda R, Suzuki Y, Ohtomi M, Sakiyama H: Selective complement c1s deficiency caused by homozygous four-base deletion in the c1s gene. Hum Genet 1998;103:415-418.
[PubMed]
17.
Suzuki Y, Ogura Y, Otsubo O, Akagi K, Fujita T: Selective deficiency of c1s associated with a systemic lupus erythematosus-like syndrome. Report of a case. Arthritis Rheum 1992;35:576-579.
[PubMed]
18.
Walport MJ, Davies KA: Complement and immune complexes. Res Immunol 1996;147:103-109.
[PubMed]
19.
Walport MJ: Complement. First of two parts. N Engl J Med 2001;344:1058-1066.
[PubMed]
20.
Walport MJ: Complement. Second of two parts. N Engl J Med 2001;344:1140-1144.
[PubMed]
21.
Kavanaugh AF, Solomon DH: Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests. Arthritis Rheum 2002;47:546-555.
[PubMed]
22.
Modur V, Feldhaus MJ, Weyrich AS, Jicha DL, Prescott SM, Zimmerman GA, McIntyre TM: Oncostatin M is a proinflammatory mediator. In vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules. J Clin Invest 1997;100:158-168.
[PubMed]
23.
Wallace PM, MacMaster JF, Rouleau KA, Brown TJ, Loy JK, Donaldson KL, Wahl AF: Regulation of inflammatory responses by oncostatin M. J Immunol 1999;162:5547-5555.
[PubMed]
24.
Tamura S, Morikawa Y, Tanaka M, Miyajima A, Senba E: Developmental expression pattern of oncostatin M receptor β in mice. Mech Dev 2002;115:127-131.
[PubMed]
25.
Gatsios P, Haubeck HD, Van de Leur E, Frisch W, Apte SS, Greiling H, Heinrich PC, Graeve L: Oncostatin M differentially regulates tissue inhibitors of metalloproteinases TIMP-1 and TIMP-3 gene expression in human synovial lining cells. Eur J Biochem 1996;241:56-63.
[PubMed]
26.
Korzus E, Nagase H, Rydell R, Travis J: The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase-1 gene expression. J Biol Chem 1997;272:1188-1196.
[PubMed]
27.
Li WQ, Zafarullah M: Oncostatin M up-regulates tissue inhibitor of metalloproteinases-3 gene expression in articular chondrocytes via de novo transcription, protein synthesis, and tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms. J Immunol 1998;161:5000-5007.
[PubMed]
28.
Uchio K, Manabe N, Kinoshita A, Tamura K, Miyamoto M, Ogura A, Yamamoto Y, Miyamoto H: Abnormalities of extracellular matrices and transforming growth factor-β1 localization in the kidney of the hereditary nephrotic mice (ICGN strain). J Vet Med Sci 1999;61:769-776.
[PubMed]
29.
Uchio K, Manabe N, Tamura K, Miyamoto M, Yamaguchi M, Ogura A, Yamamoto Y, Miyamoto H: Decreased matrix metalloproteinase activity in the kidneys of hereditary nephrotic mice (ICGN strain). Nephron 2000;86:145-151.
[PubMed]
30.
Uchio K, Sawada K, Manabe N: Expression of macrophage metalloelastase (MMP-12) in podocytes of hereditary nephrotic mice (ICGN strain). J Vet Med Sci 2009;71:305-312.
[PubMed]
31.
Uchio-Yamada K, Manabe N, Goto Y, Anann S, Yamamoto Y, Takano K, Ogura A, Matsuda J: Decreased expression of matrix metalloproteinases and tissue inhibitors of metalloproteinase in the kidneys of hereditary nephrotic (ICGN) mice. J Vet Med Sci 2005;67:35-41.
[PubMed]
32.
Uchio-Yamada K, Manabe N, Yamaguchi M, Akashi N, Goto Y, Yamamoto Y, Ogura A, Miyamoto H: Localization of extracellular matrix receptors in ICGN mice, a strain of mice with hereditary nephrotic syndrome. J Vet Med Sci 2001;63:1171-1178.
[PubMed]
33.
Segerer S, Mac KM, Regele H, Kerjaschki D, Schlondorff D: Expression of the C-C chemokine receptor 5 in human kidney diseases. Kidney Int 1999;56:52-64.
[PubMed]
34.
Teramoto K, Negoro N, Kitamoto K, Iwai T, Iwao H, Okamura M, Miura K: Microarray analysis of glomerular gene expression in murine lupus nephritis. J Pharmacol Sci 2008;106:56-67.
[PubMed]
35.
Hawkins NJ, Ward RL, Wakefield D: Cytokine-mediated induction of HLA antigen expression on human glomerular mesangial cells. Cell Immunol 1994;155:493-500.
[PubMed]
36.
Ikeda M, Minota S, Kano S: Regulation of MHC class I expression by inflammatory cytokines in rat mesangial cells. Nephron 1997;76:90-95.
[PubMed]
37.
Rohn WM, Lee YJ, Benveniste EN: Regulation of class II MHC expression. Crit Rev Immunol 1996;16:311-330.
[PubMed]
38.
Londhe P, Davie JK: Gamma interferon modulates myogenesis through the major histocompatibility complex class II transactivator, CIITA. Mol Cell Biol 2011;31:2854-2866.
[PubMed]
39.
Mazumder B, Mukhopadhyay CK, Prok A, Cathcart MK, Fox PL: Induction of ceruloplasmin synthesis by IFN-γ in human monocytic cells. J Immunol 1997;159:1938-1944.
[PubMed]
40.
Beers C, Honey K, Fink S, Forbush K, Rudensky A: Differential regulation of cathepsin S and cathepsin L in interferon-γ-treated macrophages. J Exp Med 2003;197:169-179.
[PubMed]
41.
Degrandi D, Konermann C, Beuter-Gunia C, Kresse A, Wurthner J, Kurig S, Beer S, Pfeffer K: Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense. J Immunol 2007;179:7729-7740.
[PubMed]
42.
Rubio N, Torres C: Interferon-γ induces proliferation but not apoptosis in murine astrocytes through the differential expression of the myc proto-oncogene family. Brain Res Mol Brain Res 1999;71:104-110.
[PubMed]
43.
Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A: Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 2000;289:2350-2354.
[PubMed]
44.
Brumell JH, Howard JC, Craig K, Grinstein S, Schreiber AD, Tyers M: Expression of the protein kinase C substrate pleckstrin in macrophages: association with phagosomal membranes. J Immunol 1999;163:3388-3395.
[PubMed]
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