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.

中文翻译：

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短链脂肪酸可通过FFA2和FFA3途径缓解腺嘌呤诱发的慢性肾脏疾病。

当人胃肠道中的结肠细菌发酵未消化的纤维时，会产生短链脂肪酸（SCFA），包括乙酸盐，丁酸盐和丙酸盐。游离脂肪酸受体2（FFA2）和FFA3是最近被鉴定为可调节炎症的SCFA受体的G蛋白偶联受体。我们之前通过体外实验表明，SCFA激活FFA2和FFA3，从而减轻人肾皮质上皮细胞的炎症。这项研究使用了腺嘌呤诱发的肾衰竭的小鼠模型，以研究SCFA是否可以预防肾损害的进展。我们还检查了这些FFA2和FFA3蛋白是否在体内这种保护机制中具有某些作用。小鼠肾脏的免疫组织化学分析表明，FFA2和FFA3蛋白主要在远端肾小管和收集小管中表达。首先，我们观察到丙酸盐的施用减轻了腺嘌呤引起的肾功能不全和病理恶化。与此相一致，炎性细胞因子和纤维化相关基因的表达降低了。此外，在FFA2-/-和FFA3-/-小鼠中，通过施用丙酸酯减轻了腺嘌呤诱导的肾损伤。因此，丙酸的施用至少部分地通过FFA2和FFA3途径显着保护了腺嘌呤诱导的肾衰竭。我们的数据表明，FFA2和FFA3是预防或延缓慢性肾脏病进展的潜在新治疗靶标。