PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis
PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis
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DOI：
10.1681/asn.2012020126
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发表时间：
2012-11-01
影响因子：
13.6
通讯作者：
Sono, Motoaki
中科院分区：
文献类型：
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作者：
Ito, Hideyuki;Yan, Xiaoxiang;Sono, Motoaki
在早期糖尿病肾病中，将PG H-2转化为PGD（2）的脂质运载蛋白型PGD（2）合酶（L-PGDS）的尿排泄增加。此外，阿霉素诱导的肾病肾小管上皮细胞中L-PGDS表达增加，表明局部产生的L-PGDS可能促进CKD的发展。在这项研究中，我们发现L-PGDS衍生的PGD（2）通过CRTH 2介导的Th 2淋巴细胞活化促进肾纤维化的进展。在小鼠模型中，在单侧输尿管梗阻（UUO）后，肾小管上皮细胞重新合成L-PGDS。L-PGDS基因敲除小鼠和CRTH 2基因敲除小鼠均表现出较少的肾纤维化，Th 2淋巴细胞向皮质的浸润减少，以及Th 2细胞因子IL-4和IL-13的产生减少。此外，在UUO后3天开始口服CRTH 2拮抗剂抑制了肾纤维化的进展。IL-4和IL-13的消融也改善了UUO肾中的肾纤维化。总之，这些数据表明，通过PGD（2）阻断CRTH 2的激活可能是减缓CKD肾纤维化进展的一种策略。
Urinary excretion of lipocalin-type PGD(2) synthase (L-PGDS), which converts PG H-2 to PGD(2), increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS derived PGD(2) contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD(2) might be a strategy to slow the progression of renal fibrosis in CKD.