Kobayashi Mamiko, Mikami Daisuke, Kimura Hideki, Kamiyama Kazuko, Morikawa Yukie, Yokoi Seiji, Kasuno Kenji, Takahashi Naoki, Taniguchi Takanobu, Iwano Masayuki
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Biochem Biophys Res Commun. 2017 Apr 29;486(2):499-505. doi: 10.1016/j.bbrc.2017.03.071. Epub 2017 Mar 18.
Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are produced predominantly by gut microbiota fermentation of dietary fiber. SCFAs are newly identified as endogenous ligands of two orphan G protein-coupled receptors, GPR41 and GPR43, which have the potential to modulate inflammation. Therefore, GPR41 and GPR43 may mediate the link between the gut microbiome status and various disease conditions including renal inflammation. This study aimed at investigating whether SCFAs activate GPR41 and GPR43, and thereby exert anti-inflammatory effects in human renal cortical epithelial cells (HRCEs) as a main component of kidney tissue. Immunohistochemical analyses of human renal biopsy specimens revealed the expression of GPR41 and GPR43 protein in the distal renal tubules and collecting tubules. TNF-α increased the expression of monocyte chemoattractant protein-1 (MCP-1), a potential fibrotic inducer, at least partly via enhancing phosphorylation of p38 and JNK in HRCEs. SCFAs, especially propionate, attenuated TNF-α- stimulated MCP-1 expression by inhibiting the phosphorylation of p38 and JNK. This inhibitory effect was considerably attenuated by an inactivator of the Gi/o-type G protein and a Gβγ (i/o) blocker, but not by a Gα (i/o) blocker. Furthermore, SCFA-mediated inhibition of MCP-1 expression was significantly blocked by siRNA-induced gene silencing of GPR41 and GPR43. In conclusion, SCFAs lowered TNF-α-induced MCP-1 expression by reducing phosphorylation of p38 and JNK in a GPR41/43-dependent manner in HRCEs, suggesting that SCFA modification may be a new therapeutic tool for preventing progression of renal inflammation and fibrosis.
短链脂肪酸（SCFAs），如乙酸盐、丙酸盐和丁酸盐，主要由膳食纤维经肠道微生物群发酵产生。SCFAs最近被确定为两种孤儿G蛋白偶联受体GPR41和GPR43的内源性配体，它们具有调节炎症的潜力。因此，GPR41和GPR43可能介导肠道微生物群状态与包括肾脏炎症在内的各种疾病状况之间的联系。本研究旨在调查SCFAs是否激活GPR41和GPR43，从而在作为肾组织主要成分的人肾皮质上皮细胞（HRCEs）中发挥抗炎作用。对人肾活检标本的免疫组织化学分析显示，GPR41和GPR43蛋白在远端肾小管和集合管中表达。肿瘤坏死因子-α（TNF-α）至少部分通过增强HRCEs中p38和JNK的磷酸化来增加单核细胞趋化蛋白-1（MCP-1，一种潜在的纤维化诱导剂）的表达。SCFAs，尤其是丙酸盐，通过抑制p38和JNK的磷酸化来减弱TNF-α刺激的MCP-1表达。这种抑制作用被Gi/o型G蛋白的失活剂和Gβγ（i/o）阻滞剂显著减弱，但未被Gα（i/o）阻滞剂减弱。此外，SCFA介导的对MCP-1表达的抑制被GPR41和GPR43的siRNA诱导基因沉默显著阻断。总之，SCFAs通过以GPR41/43依赖的方式降低HRCEs中p38和JNK的磷酸化来降低TNF-α诱导的MCP-1表达，表明SCFA修饰可能是预防肾脏炎症和纤维化进展的一种新的治疗工具。
