Pharmacologic Blockade of 15-PGDH Protects Against Acute Renal Injury Induced by LPS in Mice
Pharmacologic Blockade of 15-PGDH Protects Against Acute Renal Injury Induced by LPS in Mice
复制标题
15-PGDH 的药理学阻断可预防 LPS 诱导的小鼠急性肾损伤
DOI：
10.3389/fphys.2020.00138
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发表时间：
2020-03-13
影响因子：
4
通讯作者：
Zhang, Huali
中科院分区：
文献类型：
--
作者：
Miao, Shuying;Lv, Caihong;Zhang, Huali
前列腺素途径在多种生理病理条件下发挥着多种作用。本研究旨在探讨前列腺素降解关键酶15-羟基前列腺素脱氢酶（15-PGDH）对脂多糖（LPS）诱导的小鼠急性肾损伤（AKI）的影响。在本研究中，雄性C57BL/6J小鼠腹腔注射LPS （10 mg/kg）。SW033291是一种有效的15-PGDH小分子抑制剂，用于研究15-PGDH抑制对lps诱导的AKI的治疗潜力。我们发现15-PGDH蛋白在lps刺激小鼠肾脏中表达上调，主要定位于肾皮质和外髓质肾小管上皮细胞的细胞质中。SW033291可提高小鼠的存活率，减轻LPS刺激小鼠的肾损伤。此外，抑制15-PGDH还能逆转lps诱导的肾细胞凋亡，增加抗凋亡蛋白Bcl-2的表达，下调Fas、caspase-3和caspase-8的表达。预处理SW033291可增强LPS刺激后肾细胞的自噬。我们的数据还显示，抑制15-PGDH可减轻小鼠肾脏脂质过氧化水平，下调LPS诱导的NADPH氧化酶亚基，但对炎症因子如IL-6、IL-1β、TNF-α和MCP-1的释放没有显著影响。我们的研究表明，抑制15-PGDH可以通过调节小鼠的凋亡、自噬和氧化应激而不是炎症来减轻lps诱导的AKI。
Prostaglandin pathway plays multiple roles in various physiological and pathological conditions. The present study aimed to investigate the effect of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in the degradation of prostaglandins, on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice. In this study, male C57BL/6J mice were injected intraperitoneally with LPS (10 mg/kg). SW033291, a potent small-molecule inhibitor of 15-PGDH, was used to investigate the therapeutic potential of 15-PGDH inhibition on LPS-induced AKI. We discovered that the expression of 15-PGDH protein was upregulated in kidneys of LPS-stimulated mice, and it was mainly localized in the cytoplasm of renal tubular epithelial cells in renal cortex and outer medulla. SW033291 administration improved the survival rates of mice and attenuated renal injury of mice that were challenged by LPS. Additionally, inhibition of 15-PGDH also reversed LPS-induced apoptosis of renal cells, increased expression of anti-apoptotic protein Bcl-2, and downregulated expression of Fas, caspase-3, and caspase-8. Pretreatment of SW033291 enhanced autophagy in kidney cells after LPS stimulation. Our data also showed that inhibition of 15-PGDH relieved the level of lipid peroxidation and downregulated NADPH oxidase subunits induced by LPS in mice kidneys but had no significant effect on the release of inflammatory factors, such as IL-6, IL-1β, TNF-α, and MCP-1. Our study demonstrated that inhibition of 15-PGDH could alleviate LPS-induced AKI by regulating the apoptosis, autophagy, and oxidative stress rather than inflammation in mice.