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

Biochem Biophys Res Commun. 2017 Apr 29;486(2):499-505. doi: 10.1016/j.bbrc.2017.03.071. Epub 2017 Mar 18.

Abstract

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.

Keywords: GPR41; GPR43; JNK; Monocyte chemoattractant protein-1; SCFA; p38.

MeSH terms

  • Cell Line
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / metabolism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fatty Acids, Volatile / metabolism
  • Fatty Acids, Volatile / pharmacology*
  • Gene Expression Regulation
  • Glomerulonephritis / genetics
  • Glomerulonephritis / metabolism
  • Glomerulonephritis / pathology
  • Humans
  • Kidney Cortex / drug effects
  • Kidney Cortex / metabolism
  • Kidney Cortex / pathology
  • Kidney Tubules, Collecting / metabolism
  • Kidney Tubules, Collecting / pathology
  • MAP Kinase Kinase 4 / genetics*
  • MAP Kinase Kinase 4 / metabolism
  • Phosphorylation / drug effects
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • CCL2 protein, human
  • Chemokine CCL2
  • FFA2R protein, human
  • FFAR3 protein, human
  • Fatty Acids, Volatile
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4