Li Rong, Yang Niansheng, Zhang Lili, Huang Yuefang, Zhang Rui, Wang Fang, Luo Mingqian, Liang Yingjie, Yu Xueqing
Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
Am J Nephrol. 2007;27(6):580-9. doi: 10.1159/000108102. Epub 2007 Sep 6.
BACKGROUND/AIMS: 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.
背景/目的：本研究调查了细胞因子信号转导的重要途径JAK/STAT在慢性肾小球疾病进展中的作用。
给BALB/c小鼠单次静脉注射阿霉素（10mg/kg），于2、4和6周后处死。在第二项研究中，于阿霉素注射5天后开始用选择性JAK2抑制剂AG490（15mg/kg，每日一次，腹腔注射）或赋形剂进行治疗。评估功能和病理指标、炎症浸润、促炎细胞因子的表达以及JAK2/STATs的磷酸化情况。
阿霉素肾病中JAK/STAT信号被激活。AG490显著抑制了JAK2、STAT1和STAT3的磷酸化（p<0.01）。与赋形剂处理的对照组相比，AG490治疗在疾病诱导2周后未降低蛋白尿，但在第6周时导致蛋白尿和血清肌酐显著降低（p<0.05）。在第6周时，AG490治疗也显著抑制了肾小球硬化、肾小管间质病变和肾脏α-SMA的表达（p<0.01）。此外，AG490抑制了MCP-1 mRNA的表达，同时伴有巨噬细胞和T细胞间质浸润减少（p<0.05）。
本研究提示JAK/STAT信号的激活参与了蛋白尿状态下肾小球疾病的进展。
