Short-chain fatty acids, GPR41 and GPR43 ligands, inhibit TNF-α-induced MCP-1 expression by modulating p38 and JNK signaling pathways in human renal cortical epithelial cells.
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.
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Mamiko
M
Kobayashi
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. Electronic address: dmikami@u-fukui.ac.jp.
Daisuke
D
Mikami
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Department of Clinical Laboratory, University of Fukui Hospital, Fukui, Japan.
Hideki
H
Kimura
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Kazuko
K
Kamiyama
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Yukie
Y
Morikawa
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Seiji
S
Yokoi
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Kenji
K
Kasuno
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Naoki
N
Takahashi
Division of Cellular Signal Transduction, Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan.
Takanobu
T
Taniguchi
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Masayuki
M
Iwano
D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005232:Fatty Acids, Volatile / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
D018932:Chemokine CCL2; D005232:Fatty Acids, Volatile; D048670:MAP Kinase Kinase 4; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C111835:CCL2 protein, human; C473103:FFAR2 protein, human; C106262:FFAR3 protein, human
GPR41; GPR43; JNK; Monocyte chemoattractant protein-1; SCFA; p38