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Published on: May 6, 2018
Inhibition of Jak/STAT signaling ameliorates mice experimental nephrotic syndrome
Rong Li1, Niansheng Yang, Lili Zhang
1Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
Background/Aims:
This study investigated the role of JAK/STAT, an important pathway for cytokine signal transduction, in the progression of chronic glomerular diseases.
Methods:
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.
Results:
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).
Conclusions:
This study suggests that activation of JAK/STAT signaling is involved in the progression of glomerular diseases with proteinuric state.
Insights
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is activated in chronic glomerular diseases. Inhibiting this pathway with AG490 reduced disease progression and kidney damage.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is crucial for cytokine signal transduction.
- Activation of JAK/STAT signaling is implicated in the progression of various chronic diseases.
Purpose of the Study:
- To investigate the role of the JAK/STAT pathway in the progression of chronic glomerular diseases.
- To evaluate the therapeutic potential of a JAK2 inhibitor in a mouse model of nephropathy.
Main Methods:
- Adriamycin-induced nephropathy model in BALB/c mice.
- Administration of the selective JAK2 inhibitor AG490 or vehicle.
- Assessment of functional markers (proteinuria, serum creatinine), pathological changes (glomerulosclerosis, tubulointerstitial lesions), inflammatory markers, and JAK/STAT pathway activation.
Main Results:
- JAK/STAT signaling was activated in adriamycin-induced nephropathy.
- AG490 treatment significantly inhibited JAK2, STAT1, and STAT3 phosphorylation.
- AG490 treatment reduced proteinuria, serum creatinine, glomerulosclerosis, tubulointerstitial lesions, and alpha-SMA expression at week 6.
- AG490 suppressed MCP-1 mRNA expression and reduced macrophage and T cell infiltration.
Conclusions:
- Activation of the JAK/STAT signaling pathway contributes to the progression of proteinuric glomerular diseases.
- Targeting JAK/STAT signaling with inhibitors like AG490 may offer a therapeutic strategy for chronic kidney diseases.
