ag-490 and Nephrotic-Syndrome

This study investigated the role of JAK/STAT, an important pathway for cytokine signal transduction, in the progression of chronic glomerular diseases.. BALB/c mice received a single intravenous injection of adriamycin (10 mg/kg) were sacrificed 2, 4 and 6 weeks later. In the second study, treatment with the selective JAK2 inhibitor AG490 (15 mg/kg, q.d., i.p.) or vehicle was started 5 days after adriamycin injection. Functional and pathologic markers, inflammatory infiltration, expression of pro-inflammatory cytokines and phosphorylation of JAK2/STATs were assessed.. JAK/STAT signaling was activated in adriamycin nephropathy. Phosphorylation of JAK2, STAT1 and STAT3 was significantly inhibited by AG490 (p <0.01). Compared to the vehicle-treated controls, AG490 treatment did not reduce proteinuria 2 weeks after induction of the disease, but resulted in significant decrease in proteinuria and serum creatinine at week 6 (p <0.05). Glomerulosclerosis, tubulointerstitial lesions and renal alpha-SMA expression were also significantly suppressed by AG490 treatment at week 6 (p < 0.01). In addition, AG490 inhibited the expression of MCP-1 mRNA, accompanied by reduced interstitial infiltration of macrophages and T cells (p <0.05).. This study suggests that activation of JAK/STAT signaling is involved in the progression of glomerular diseases with proteinuric state.

Topics: Animals; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Janus Kinase 2; Kidney; Male; Mice; Mice, Inbred BALB C; Nephrotic Syndrome; Phosphorylation; Signal Transduction; STAT Transcription Factors; STAT1 Transcription Factor; STAT3 Transcription Factor; Tyrphostins