ag-490 and Lupus-Nephritis

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.

Topics: Animals; Antibodies, Antinuclear; Disease Models, Animal; Disease Progression; DNA; Enzyme Inhibitors; Female; Inflammation; Janus Kinase 2; Janus Kinases; Kidney; Lupus Nephritis; Mice; Mice, Inbred MRL lpr; Phosphorylation; Salivary Glands; Signal Transduction; STAT Transcription Factors; STAT1 Transcription Factor; Tyrphostins