Departmental Bulletin Paper Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells

Yisireyili, Maimaiti  ,  Takeshita, Kyosuke  ,  Saito, Shinichi  ,  Murohara, Toyoaki  ,  Niwa, Toshimitsu

79 ( 4 )  , pp.477 - 486 , 2017-11 , Nagoya University Graduate School of Medicine, School of Medicine
ISSN:0027-7622
Description
Indoxyl sulfate (IS) induces fibrosis and inflammation in kidneys via oxidative stress through the induction of transforming growth factor-β1 (TGF-β1) and monocyte chemotactic protein-1 (MCP-1). Furthermore, IS is a potent endogenous agonist for aryl hydrocarbon receptor (AHR), which regulates the transcription of genes such as cytochrome P450 (CYP) 1A1. Indole-3-propionic acid (IPA) is an antioxidant and has been reported to be neuroprotective. We determined whether IPA suppresses IS-induced expression of AHR, CYP1A1, TGF-β1, and MCP-1 in proximal tubular cells. The effects of IS on the expression of AHR, CYP1A1, TGF-β1, and MCP-1 were studied using normotensive rats and hypertensive rats. The effects of IPA on IS-induced expression of AHR, CYP1A1, TGF-β1, and MCP-1 were studied using proximal tubular cells (HK-2). Furthermore, the effects of IPA on IS-induced expression and phosphorylation of signal transducer and activator of transcription 3 (Stat3) were studied in HK-2 cells. Administration of IS induced the expression of AHR, CYP1A1, TGF-β1, and MCP-1 in the tubular cells of rat kidneys. IPA significantly suppressed IS-induced mRNA and protein expression of AHR, CYP1A1, TGF-β1, and MCP-1 in HK-2 cells. IPA suppressed the IS-induced expression and phosphorylation of Stat3 in HK-2 cells. Furthermore, knockdown of Stat3 inhibited the IS-induced mRNA and protein expression of AHR, CYP1A1, TGF-β1, and MCP-1 in HK-2 cells. In conclusion, IPA suppressed the IS-induced expression of AHR, CYP1A1, TGF-β1, and MCP-1 through suppression of Stat3 in proximal tubular cells. Thus, IPA suppresses IS-induced expression of fibrotic and inflammatory genes in proximal tubular cells.
This study was supported in part by JSPS research grant (JSPS KAKENHI Grant Number 15J00397).
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