Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis.
Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis.
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DOI：
10.1016/j.bbadis.2022.166456
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发表时间：
2022-10-01
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影响因子：
--
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中科院分区：
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尽管大麻素受体(CB)被认为是肾脏纤维化的靶标，但内源性大麻素anandamide(AEA)及其主要水解酶脂肪酸酰胺水解酶(FAAH)在肾纤维化形成中的作用尚不清楚。本研究使用小鼠缺血再灌注后肾损伤(PIR)模型来验证FAAH参与肾纤维化形成的假说。结果表明，PIR大鼠肾脏近端小管FAAH表达上调，肾脏AEA水平降低。Faah基因敲除小鼠恢复了降低的AEA水平，并改善了PIR引发的血尿素氮、血浆肌酐以及肾脏促纤维化标志物和损伤的增加。相应地，选择性FAAH抑制剂PF-04457845可抑制转化生长因子-β1(TGF1)诱导的人近端肾小管上皮细胞系(HK-2细胞)和小鼠原代培养的肾小管上皮细胞的促纤维化标志物。在HK-2细胞中，siRNA对FAAH的抑制作用与PF-04457845相似。从FAAH−/−小鼠分离的肾小管上皮细胞进一步验证了对转化生长因子-β1诱导的损伤的保护作用。CB1或CB2受体拮抗剂和外源性FAAH代谢产物花生四烯酸不能逆转FAAH失活对HK-2细胞的保护作用。然而，底物选择性的AEA-环氧合酶-2(COX-2)通路抑制剂显著抑制FAAH抑制的抗纤维化作用。此外，AEA-COX-2代谢产物前列胺E2具有抗纤维化作用。这些结果表明，FAAH的激活和随后AEA的减少参与了肾纤维化的形成，FAAH的抑制通过AEA-COX-2途径恢复减少的AEA来保护肾细胞不依赖CB受体的纤维化形成。
Although cannabinoid receptors (CB) are recognized as targets for renal fibrosis, the roles of endogenous cannabinoid anandamide (AEA) and its primary hydrolytic enzyme, fatty acid amide hydrolase (FAAH), in renal fibrogenesis remain unclear. The present study used a mouse model of post-ischemia-reperfusion renal injury (PIR) to test the hypothesis that FAAH participates in the renal fibrogenesis. Our results demonstrated that PIR showed upregulated expression of FAAH in renal proximal tubules, accompanied with decreased AEA levels in kidneys. Faah knockout mice recovered the reduced AEA levels and ameliorated PIR-triggered increases in blood urea nitrogen, plasma creatinine as well as renal profibrogenic markers and injuries. Correspondingly, a selective FAAH inhibitor, PF-04457845, inhibited the transforming growth factor-beta 1 (TGF-β1)–induced profibrogenic markers in human proximal tubular cell line (HK-2 cells) and mouse primary cultured tubular cells. Knockdown of FAAH by siRNA in HK-2 cells had similar effects as PF-04457845. Tubular cells isolated from Faah−/− mice further validated the protection against TGF-β1–induced damages. The CB 1 or CB2 receptor antagonist and exogenous FAAH metabolite arachidonic acid failed to reverse the protective effects of FAAH inactivation in HK-2 cells. However, a substrate-selective inhibitor of AEA-cyclooxygenase-2 (COX-2) pathway significantly suppressed the anti-profibrogenic actions of FAAH inhibition. Further, the AEA-COX-2 metabolite, prostamide E2 exerted anti-fibrogenesis effect. These findings suggest that FAAH activation and the consequent reduction of AEA contribute to the renal fibrogenesis, and that FAAH inhibition protects against fibrogenesis in renal cells independently of CB receptors via the AEA-COX-2 pathway by the recovery of reduced AEA.
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影响因子：
25
作者：
Hermanson, Daniel J.;Hartley, Nolan D.;Gamble-George, Joyonna;Brown, Naoko;Shonesy, Brian C.;Kingsley, Phillip J.;Colbran, Roger J.;Reese, Jeffrey;Marnett, Lawrence J.;Patel, Sachin
通讯作者：
Patel, Sachin
影响因子：
5.3
作者：
Dao, Myriam;Lecru, Lola;Francois, Helene
通讯作者：
Francois, Helene
影响因子：
3.2
作者：
Dobrzynska，Izabela;Szachowicz-Petelska，Barbara;Skrzydlewskac，ElZbieta
通讯作者：
Skrzydlewskac，ElZbieta
影响因子：
6.1
作者：
Barutta, Federica;Grimaldi, Serena;Gruden, Gabriella
通讯作者：
Gruden, Gabriella
DOI：
10.1124/jpet.111.180257
发表时间：
2011-07-01
影响因子：
3.5
作者：
Ahn, Kay;Smith, Sarah E.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.