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Asiatic acid prevents renal fibrosis in UUO rats via promoting the production of 15d-PGJ2, an endogenous ligand of PPAR-γ.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-11-08 , DOI: 10.1038/s41401-019-0319-4 Zhi-Hao Zhang 1, 2 , Jun-Qiu He 1 , Ying-Yong Zhao 2 , Hua-Chao Chen 1 , Ning-Hua Tan 1
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-11-08 , DOI: 10.1038/s41401-019-0319-4 Zhi-Hao Zhang 1, 2 , Jun-Qiu He 1 , Ying-Yong Zhao 2 , Hua-Chao Chen 1 , Ning-Hua Tan 1
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Renal fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Recently, asiatic acid (AA), a triterpenoid compound from Chinese medicine Centella asiatica, has been found to attenuate renal fibrosis. In the current study, we explored the mechanisms underlying antifibrotic effect of AA on UUO model. SD rats and ICR mice were subjected to unilateral ureteral occlusion (UUO) surgery. Prior the surgery, rats were administered AA (10 mg·kg-1 per day, ig) for 7 days, whereas the mice received AA (15 mg·kg-1 per day, ig) for 3 days. UUO group displayed significant degree of renal dysfunction, interstitial fibrosis, oxidative stress, and activation of the TGF-β/Smad and Wnt/β-catenin signaling pathway in the kidney, these pathological changes were greatly ameliorated by pretreatment with AA. In addition, we found that co-treatment with GW9662, a selective PPAR-γ antagonist (1 mg·kg-1 per day, ip) for 7 days, abolished the protective effects of AA. We further revealed that AA pretreatment did not significantly change the expression levels of PPAR-γ in the kidney, but markedly increase the plasma levels of 15d-PGJ2, an endogenous ligand of PPAR-γ. In UUO mice, pretreatment with 15d-PGJ2 (24 μg·kg-1 per day, ip, for 7 days) produced similar protective effect as AA. Moreover, AA pretreatment upregulated the expression levels of active, nuclear-localized SREBP-1 (nSREBP-1), whereas fatostatin, a specific inhibitor of SREBP-1, decreased the expression of nSREBP-1, as well as the level of 15d-PGJ2. These results provide new insight into the antifibrotic mechanism of AA and endogenous metabolites might become a new clue for investigation of drug mechanism.
中文翻译：
积雪草酸通过促进15d-PGJ2（一种PPAR-γ的内源性配体）的产生来预防UUO大鼠的肾纤维化。
肾纤维化是各种进行性慢性肾脏病（CKD）的必然结果。最近，已发现中草药积雪草中的三萜类化合物积雪草酸（AA）可减轻肾纤维化。在当前的研究中，我们探讨了AA对UUO模型抗纤维化作用的潜在机制。对SD大鼠和ICR小鼠进行单侧输尿管闭塞（UUO）手术。手术前，给大鼠服用AA（每天10 mg·kg-1，ig）7天，而给小鼠服用3天（每天15 mg·kg-1，ig）。UUO组显示出严重程度的肾功能不全，间质纤维化，氧化应激以及肾中TGF-β/ Smad和Wnt /β-catenin信号通路的激活，而用AA预处理可大大改善这些病理变化。此外，我们发现与选择性PPAR-γ拮抗剂GW9662（每天1 mg·kg-1，腹膜内）联合治疗7天，可以消除AA的保护作用。我们进一步揭示，AA预处理并未显着改变肾脏中PPAR-γ的表达水平，但显着增加了PPAR-γ的内源性配体15d-PGJ2的血浆水平。在UUO小鼠中，用15d-PGJ2进行预处理（每天24μg·kg-1，腹膜内注射7天）可产生与AA相似的保护作用。此外，AA预处理上调了活跃的核定位SREBP-1（nSREBP-1）的表达水平，而Fatostatin（一种SREBP-1的特异性抑制剂）降低了nSREBP-1的表达以及15d- PGJ2。
更新日期：2019-11-08
中文翻译：
积雪草酸通过促进15d-PGJ2（一种PPAR-γ的内源性配体）的产生来预防UUO大鼠的肾纤维化。
肾纤维化是各种进行性慢性肾脏病（CKD）的必然结果。最近，已发现中草药积雪草中的三萜类化合物积雪草酸（AA）可减轻肾纤维化。在当前的研究中，我们探讨了AA对UUO模型抗纤维化作用的潜在机制。对SD大鼠和ICR小鼠进行单侧输尿管闭塞（UUO）手术。手术前，给大鼠服用AA（每天10 mg·kg-1，ig）7天，而给小鼠服用3天（每天15 mg·kg-1，ig）。UUO组显示出严重程度的肾功能不全，间质纤维化，氧化应激以及肾中TGF-β/ Smad和Wnt /β-catenin信号通路的激活，而用AA预处理可大大改善这些病理变化。此外，我们发现与选择性PPAR-γ拮抗剂GW9662（每天1 mg·kg-1，腹膜内）联合治疗7天，可以消除AA的保护作用。我们进一步揭示，AA预处理并未显着改变肾脏中PPAR-γ的表达水平，但显着增加了PPAR-γ的内源性配体15d-PGJ2的血浆水平。在UUO小鼠中，用15d-PGJ2进行预处理（每天24μg·kg-1，腹膜内注射7天）可产生与AA相似的保护作用。此外，AA预处理上调了活跃的核定位SREBP-1（nSREBP-1）的表达水平，而Fatostatin（一种SREBP-1的特异性抑制剂）降低了nSREBP-1的表达以及15d- PGJ2。
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