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Ah receptor activation coordinates intestinal epithelial cell programing

ABSTRACT: The intestinal epithelium undergoes differentiation into multiple cell types and undergoes rapid cellular turnover. The Aryl hydrocarbon receptor (AHR) is a sensor of small molecules found either in the diet or due to microbiota metabolism. Ahr and Cyp1a1 exhibits the highest expression in the duodenum. Germ-free mice display similar levels of Cyp1a1 expression suggesting that in mice diet is the primary source of AHR activation potential. The lack of AHR expression alters; the rate of transit down the small intestine, barrier function, and proliferative index. In Ahr-/- mouse duodenum there is also a decrease in goblet cells, mucin levels and expression of gene expression linked to epithelial cell differentiation. AHR activation with indolo[3,2b]carbazole or broccoli; increases expression of differentiation markers, decreases epithelial proliferative index and increases goblet cell number. Math1 and Klf4 are AHR target genes that are linked to development of the secretory cell linkage. Collectively, our study indicates that dietary activation of the AHR leads to altered epithelial programing leading to increased goblet cells and decreased cell shedding.

ORGANISM(S): Mus musculus

PROVIDER: GSE176330 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:Indoxyl sulfate (IS) is a uremic toxin and ligand of the aryl-hydrocarbon receptor (Ahr), a transcriptional regulator. Elevated serum IS may contribute to the progression of kidney disease. Therefore, we assessed mouse podocyte damage mediated by IS. Ahr was predominantly localized to the podocyte nucleus in vivo and in vitro. In isolated glomeruli, IS-exposure for 2 – 24 h induced Cyp1a1 expression, the most sensitive biomarker of Ahr activation. Mice exposed to IS for 4–8 weeks exhibited microalbuminuria, and mild glomerular injury characterized by ischemic changes, partial podocyte foot process effacement, as well as vascular and tubulointerstitial damage. Chronically IS-exposed kidneys exhibited decreased mRNA, decreased protein levels, and altered staining patterns for podocin, synaptopodin, and non-muscle myosin IIA (Myh9). Immortalized podocytes, upon differentiation, exhibited Ahr nuclear translocation beginning 30 min after 1 mM IS-exposure. At 2 h, there was a dose-dependent decrease in podocyte mRNA expression of WT1, Podxl, Snypo, Myh9, Actn4, and Cd2ap. After 24 h of exposure to IS, podocytes were smaller, had fewer actin/Myh9 fibers, and decreased viability. Ahr-RNAi decreased mRNA expression of podocyte-specific proteins and inhibited Cyp1a1 induction by IS-exposure. Combinations of Ahr-RNAi and IS-exposure further decreased Myh9 expression. In immortalized human podocytes, IS treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. Thus, chronic IS-exposure causes glomerular damage by activating Ahr, altering podocyte function, differentiation, and morphology, and inducing a pro-inflammatory phenotype. Podocyte cells treated with Indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand, mediates progressive glomerular disease by damaging podocytes Human podocyte cell line treated with or without 3-Indoxyl sulfate (1mM/0.1%DMSO) in three replications

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Ah receptor activation coordinates intestinal epithelial cell programing

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