Delayed inhibition of p38 mitogen-activated protein kinase ameliorates renal fibrosis in obstructive nephropathy
Delayed inhibition of p38 mitogen-activated protein kinase ameliorates renal fibrosis in obstructive nephropathy
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DOI：
10.1093/ndt/gfn309
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发表时间：
2008-08-01
影响因子：
6.1
通讯作者：
Hamaoka, Kenji
中科院分区：
文献类型：
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作者：
Nishida, Masashi;Okumura, Yasuko;Hamaoka, Kenji
背景资料。P38丝裂原活化蛋白激酶(MAPK)通路是一条重要的细胞内信号通路，参与促炎和促纤维化介质的产生。以前的报道表明p38 MAPK激活在肾纤维化中的作用。我们在单侧输尿管梗阻(UUO)的晚期(7-14天)给予选择性p38αMAPK抑制剂FR167653，并在14天检测肾脏的p38和p38磷酸化MAPK蛋白水平、肾纤维化程度、肌成纤维细胞聚集和巨噬细胞浸润程度以及肾组织中转化生长因子-β1和α1(I)胶原的mRNA水平。在UUO后第14天，FR167653治疗导致磷酸化p38MAPK水平显著降低，同时纤维化减轻。FR167653治疗后，虽然肌成纤维细胞积聚减少，α1(I)胶原基因表达减少，但间质巨噬细胞数和转化生长因子-β1基因表达水平无明显变化。这些结果表明，阻断p38MAPK是一个有吸引力的治疗靶点，即使在出现已建立的纤维化之后。
Background. The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signalling pathway involved in the production of proinflammatory and profibrotic mediators. Previous reports indicated the role of p38 MAPK activation in renal fibrosis.Methods. We administered a selective p38 alpha MAPK inhibitor, FR167653, in a mouse model of unilateral ureteral obstruction (UUO) during the late stage (Days 7-14) after UUO, and the kidneys were examined at Day 14. p38 and phospho-p38 MAPK protein levels, the degree of renal fibrosis, the degree of myofibroblast accumulation and macrophage infiltration, and mRNA levels for TGF-beta 1 and alpha 1(I) collagen in the kidneys were assessed.Results. FR167653 treatment caused marked decreases in phospho-p38 MAPK levels along with decreased fibrosis at Day 14 after UUO. Although myofibroblast accumulation and alpha 1(I) collagen mRNA level were decreased, no significant change was observed in the number of interstitial macrophages and TGF-beta 1 mRNA level with FR167653 treatment.Conclusions. These results suggest that p38 MAPK blockade is an appealing therapeutic target, even after the emergence of established fibrosis.