The intrinsic prostaglandin E2-EP4 system of the renal tubular epithelium limits the development of tubulointerstitial fibrosis in mice
The intrinsic prostaglandin E2-EP4 system of the renal tubular epithelium limits the development of tubulointerstitial fibrosis in mice
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DOI：
10.1038/ki.2012.115
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发表时间：
2012-07-01
影响因子：
19.6
通讯作者：
Ushikubi, Fumitaka
中科院分区：
文献类型：
--
作者：
Nakagawa, Naoki;Yuhki, Koh-ichi;Ushikubi, Fumitaka
肾脏中的炎症反应导致肾小管间质纤维化，这是慢性肾脏疾病的常见特征。在此我们研究了前列腺素E-2（PGE（2））在肾小管间质纤维化发展中的作用。在野生型小鼠的肾脏中，单侧输尿管梗阻导致进行性肾小管间质纤维化伴巨噬细胞浸润和肌成纤维细胞增殖。这伴随着考克斯-2和PGE（2）受体亚型EP 4 mRNA的上调。然而，在EP 4基因敲除小鼠的肾脏中，阻塞诱导的组织学改变显著增强。相比之下，EP 4特异性激动剂显著减弱了野生型小鼠肾脏中的这些改变。输尿管梗阻后野生型小鼠肾脏中巨噬细胞趋化因子和促纤维化生长因子的mRNA上调。这在EP 4敲除小鼠的肾脏中显著增强，并被EP 4激动剂抑制，但仅在野生型小鼠的肾脏中。值得注意的是，考克斯-2和MCP-1蛋白，以及EP 4 mRNA，定位于肾小管上皮细胞在输尿管梗阻后。在培养的肾成纤维细胞中，另一种EP 4特异性激动剂显著抑制PDGF诱导的增殖和促纤维化结缔组织生长因子的产生。因此，肾小管上皮中的内源性PGE（2）-EP 4系统通过抑制炎症反应限制肾小管间质纤维化的发展。Kidney International（2012）82，158-171; doi：10.1038/ki.2012.115; 2012年4月18日在线发表
Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E-2 (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast proliferation. This was accompanied by an upregulation of COX-2 and PGE(2) receptor subtype EP4 mRNAs. In the kidneys of EP4 gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP4-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP4-knockout mice and suppressed by the EP4 agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP4 mRNA, were localized in renal tubular epithelial cells after ureteral obstruction. In cultured renal fibroblasts, another EP4-specific agonist significantly inhibited PDGF-induced proliferation and profibrotic connective tissue growth factor production. Hence, an endogenous PGE(2)-EP4 system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses. Kidney International (2012) 82, 158-171; doi: 10.1038/ki.2012.115; published online 18 April 2012