Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Clin Immunol. 2014 Jan;150(1):78-87. doi: 10.1016/j.clim.2013.11.003. Epub 2013 Nov 13.
Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3(+/-) mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3(+/-) mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3(+/-) mice, while it was aggravated by pre-treatment with pyridine6-PGLA. Although there were no differences in renal mRNA levels of TGF-β and collagens between wild and SOCS3(+/-) mice, MMP-2 activity was enhanced in SOCS3(+/-) UUO mice. Activated MMP-2 was completely suppressed by pyridine6-PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.
炎症参与了肾脏纤维化，这是肾脏疾病的共同终末途径。为了阐明 JAK/STAT/SOCS 系统如何参与肾脏纤维化，在 BALB/c 或 SOCS3(+/-) 小鼠中诱导 UUO，并在存在或不存在 JAK 抑制剂结合纳米颗粒（吡啶 6-PGLA）的情况下进行研究。UUO 增加了 pSTAT3，随后增加了阻塞肾脏中的 SOCS3 水平。SOCS3(+/-) 小鼠中的 pSTAT3 水平进一步增加。SOCS3(+/-) 小鼠中的 UUO 诱导的肾脏纤维化明显受到抑制，而吡啶 6-PGLA 的预处理则加剧了这种抑制。尽管野生型和 SOCS3(+/-) 小鼠之间的肾脏 TGF-β 和胶原 mRNA 水平没有差异，但 SOCS3(+/-)UUO 小鼠中的 MMP-2 活性增强。吡啶 6-PGLA 预处理完全抑制了活化的 MMP-2。TNF-α 是 JAK/STAT 激活剂之一，它增加了 pSTAT3 水平，随后诱导了近端肾小管细胞中 MMP-2 的激活。这些结果表明，JAK/STAT3 信号通路可能通过 MMP-2 的激活在 UUO 中的肾脏纤维化修复过程中发挥作用。
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