Jak/STAT signaling is involved in the inflammatory infiltration of the kidneys in MRL/lpr mice.
Cytokines are known to play an important role in the pathogenesis of lupus nephritis (LN) and the Jak/STAT (Janus kinase-signal transducer and activator of transcription factor) pathway is important in mediating signal transduction of cytokines. This study examined the pathogenic role of Jak/STAT signaling in LN. MRL/lpr mice were either treated with a selective Jak2 inhibitor tyrphostin AG490 or with vehicle alone from 12 weeks of age until being sacrificed at week 20. AG490 significantly inhibited the phosphorylation of Jak2 and STAT1 (p < 0.05). Compared with the vehicle-treated mice, AG490 treatment significantly reduced proteinuria, improved renal function and suppressed histological lesions of the kidneys and salivary glands (p < 0.05). AG490 treatment significantly inhibited the renal expression of monocyte chemotactic protein (MCP)-1, interferon (IFN)-gamma and class II MHC, which was accompanied by reduced renal infiltration of T cells and macrophages (p < 0.05). In addition, AG490 treatment resulted in a decrease in serum anti-double-stranded DNA (anti-dsDNA) antibody and attenuated the deposition of IgG and C3 in the kidneys (p < 0.05). This study demonstrated that Jak/STAT pathway is implicated in the progression of renal inflammation in MRL/lpr mice and targeting this pathway may provide a potential therapeutic approach for LN.
Wang
S
S
Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Yang
N
N
Zhang
L
L
Huang
B
B
Tan
H
H
Liang
Y
Y
Li
Y
Y
Yu
X
X
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008181:Lupus Nephritis / Q000503:physiopathology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010766:Phosphorylation; D050791:STAT Transcription Factors / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
D000974:Antibodies, Antinuclear; D004791:Enzyme Inhibitors; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D004247:DNA; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053612:Janus Kinases