Short-chain fatty acid mitigates adenine-induced chronic kidney disease via FFA2 and FFA3 pathways
Short-chain fatty acid mitigates adenine-induced chronic kidney disease via FFA2 and FFA3 pathways
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DOI：
10.1016/j.bbalip.2020.158666
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发表时间：
2020-06-01
影响因子：
4.8
通讯作者：
Iwano, Masayuki
中科院分区：
文献类型：
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作者：
Mikami, Daisuke;Kobayashi, Mamiko;Iwano, Masayuki
短链脂肪酸（SCFAs），包括醋酸盐、丁酸盐和丙酸盐，是人类胃肠道中的结肠细菌发酵未消化纤维时产生的。游离脂肪酸受体2 （FFA2）和FFA3是最近发现的可调节炎症的g蛋白偶联受体。我们之前通过体外实验表明，SCFAs激活FFA2和FFA3，从而减轻人肾皮质上皮细胞的炎症。本研究使用腺嘌呤诱导的小鼠肾功能衰竭模型来研究SCFAs是否可以阻止肾损害的进展。我们还研究了这些FFA2和FFA3蛋白是否在体内的这种保护机制中起一定的作用。小鼠肾脏免疫组化分析显示，FFA2和FFA3蛋白主要表达于肾远端小管和集合小管。首先，我们观察到丙酸减轻了腺嘌呤引起的肾功能障碍和病理恶化。与此一致的是，炎症细胞因子和纤维化相关基因的表达减少。此外，在FFA2（-/-）和FFA3（-/-）小鼠中，丙酸给药对腺嘌呤诱导的肾损害的缓解作用显著减弱。因此，丙酸盐的施用至少部分通过FFA2和FFA3途径显著保护腺嘌呤诱导的肾功能衰竭。我们的数据表明，FFA2和FFA3是预防或延缓慢性肾脏疾病进展的潜在新治疗靶点。
Short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, are produced when colonic bacteria in the human gastrointestinal tract ferment undigested fibers. Free fatty acid receptor 2 (FFA2) and FFA3 are G-protein-coupled receptors recently identified as SCFA receptors that may modulate inflammation. We previously showed through in vitro experiments that SCFAs activate FFA2 and FFA3, thereby mitigating inflammation in human renal cortical epithelial cells. This study used a murine model of adenine-induced renal failure to investigate whether or not SCFAs can prevent the progression of renal damage. We also examined whether or not these FFA2 and FFA3 proteins have some roles in this protective mechanism in vivo. Immunohistochemical analyses of mouse kidneys showed that FFA2 and FFA3 proteins were expressed mainly in the distal renal tubules and collecting tubules. First, we observed that the administration of propionate mitigated the renal dysfunction and pathological deterioration caused by adenine. Consistent with this, the expression of inflammatory cytokines and fibrosis-related genes was reduced. Furthermore, the mitigation of adenine-induced renal damage by the administration of propionate was significantly attenuated in FFA2(-/-) and FFA3(-/-) mice. Therefore, the administration of propionate significantly protects against adenine-induced renal failure, at least in part, via the FFA2 and FFA3 pathways. Our data suggest that FFA2 and FFA3 are potential new therapeutic targets for preventing or delaying the progression of chronic kidney disease.