Effects of a spleen tyrosine kinase inhibitor on progression of the lupus nephritis in mice

Maki Kitai; Noboru Fukuda; Takahiro Ueno; Morito Endo; Takashi Maruyama; Masanori Abe; Kazuyoshi Okada; Masayoshi Soma; Koichi Matsumoto

doi:10.1016/j.jphs.2017.02.015

Effects of a spleen tyrosine kinase inhibitor on progression of the lupus nephritis in mice

J Pharmacol Sci. 2017 May;134(1):29-36. doi: 10.1016/j.jphs.2017.02.015. Epub 2017 Mar 25.

Authors

Maki Kitai¹, Noboru Fukuda², Takahiro Ueno¹, Morito Endo³, Takashi Maruyama¹, Masanori Abe¹, Kazuyoshi Okada¹, Masayoshi Soma⁴, Koichi Matsumoto¹

Affiliations

¹ Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
² Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; Research Center of Nihon University, Tokyo, Japan. Electronic address: fukuda.noboru@nihon-u.ac.jp.
³ Faculty of Human Health Science, Hachinohe Gakuin University, Hachinohe, Aomori, Japan.
⁴ Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

PMID: 28479222
DOI: 10.1016/j.jphs.2017.02.015

Abstract

The Fc receptors (FcR) have pivotal roles in the pathogenesis of the autoimmune glomerulonephritis. We therefore investigated the effects of a Syk inhibitor on the progression of lupus nephritis and SH3 domain binding protein 2 and p38MAP kinase signalings in mice. NZB/W F1 mice, a model of lupus nephritis, received a Syk inhibitor R406. Western blotting and immunohistochemistry revealed that R406 treatment significantly delayed the appearance of proteinuria, histologically improved their glomerulosclerosis and inhibited the increased the expression of MCP-1 and TGF-β1 mRNAs and the nephrin and podocin proteins in the kidney. The treatment suppressed the phosphorylation of 3BP2 in white blood cells from the spleen and significantly inhibited the phosphorylation of p38MAPK in the kidney but did not affect expression of neonatal Fc receptor. These findings indicate the important roles and mechanisms of Fcγ receptors I and III in the development of autoimmune glomerulonephritis and suggest the possible application of Syk inhibitors as novel medicines for the glomerulonephritis.

Keywords: 3BP2; Fc receptor; Lupus nephritis; Syk; p38MAP kinase.

MeSH terms

Administration, Oral
Animals
Chemokine CCL2 / genetics
Chemokine CCL2 / metabolism
Disease Progression
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / pharmacology*
Female
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Kidney / drug effects
Kidney / immunology
Kidney / pathology
Lupus Nephritis / drug therapy*
Lupus Nephritis / immunology
Lupus Nephritis / pathology
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Inbred NZB
Oxazines / administration & dosage
Oxazines / pharmacology*
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology*
Proteinuria / prevention & control
Pyridines / administration & dosage
Pyridines / pharmacology*
Receptors, IgG / metabolism
Signal Transduction
Syk Kinase / antagonists & inhibitors*
Syk Kinase / metabolism*
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

CCL2 protein, human
Chemokine CCL2
Enzyme Inhibitors
Fcgr1 protein, mouse
Fcgr3 protein, mouse
Intracellular Signaling Peptides and Proteins
Membrane Proteins
N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
NPHS2 protein
Oxazines
Protein Kinase Inhibitors
Pyridines
Receptors, IgG
Transforming Growth Factor beta1
Syk Kinase
Syk protein, mouse
p38 Mitogen-Activated Protein Kinases