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Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Promotes Regeneration of Corneal Epithelial Cells via NR4A1 Signaling Pathway

ABSTRACT: PACAP is a neuropeptide that promotes lacrimal fluid secretion, but its direct action on corneal injury remains to be clarified. Therefore, the effect of PACAP on corneal epithelial repair was clarified using mouse corneal wound-injury model and human corneal epithelial culture cells. PAC1-R mRNA and its immunoreactivity was detected in mouse and corneal epithelium. In corneal wound-injury model mice, PACAP eye drop significantly reduced the injured area at 12 hours, and the effect was cancelled by co-treatment with the PACAP receptor antagonist. PACAP heterozygous and PAC1-R knockout mouse delayed the corneal healing. Although surgical removal of the lacrimal gland attenuates corneal healing, PACAP eye drop on the eyes significantly recuperated corneal damage. In an in-vitro study, PACAP treatment in human corneal epithelial cells significantly decreased the injury area induced by scratching. PACAP treatment in the in-vitro human corneal epithelial cell experiments significantly reduced the area of injury and abolished the corneal repair effect due to the inhibitory effect of Ara-C on proliferation. DNA whole-genome microarray analysis suggested that the nuclear receptor NR4A1 is an important factor in corneal epithelial proliferation, and THPN, which induces nuclear export of NR4A1, suppressed PACAP-induced proliferation of human corneal epithelial cells and the repair effect of mouse corneal epithelium. These data suggest that PACAP stimulates corneal repair by corneal epithelial proliferation via PAC1-R and NR4A1 transcriptional activity. PACAP could be a good candidate as an eye-drop medication for corneal injury disease including dry eye syndrome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290267 | GEO | 2025/02/27

REPOSITORIES: GEO

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Project description:The bovine chromaffin cell (BCC) is a unique modelM-bM-^@M-^Ta highly homogeneous and accessible neuroendocrine cellM-bM-^@M-^Tin which to study gene regulation through first messenger-initiated signaling pathways that are specific to post-mitotic cells. BCCs were treated with tumor necrosis factor (TNF) or pituitary adenylate cyclase activating polypeptide (PACAP), two critical regulators of neural cell transcriptional programming during inflammation that act on TNFR2 and PAC1 receptors, respectively, in post-mitotic neuroendocrine cells. Transcripts which were significantly up regulated by either or both first messenger were identified from microarray analysis using two bovine oligonucleotide arrays (Affymetrix and Agilent) followed by statistical analysis with Partek Genomic suite. Microarray data were combined from the two arrays using qRT-PCR sampling validation, and the first-messenger transcriptome derived from TNF and PACAP signaling were compared. More than 90 percent of the genes up regulated either by TNF or PACAP were specific to a single first messenger. BioBase suite, DIRE and Opossum were used to identify common promoter/enhancer response elements that control the expression of TNF- or PACAP-stimulated genes. Bioinformatic analysis revealed that distinct groups of transcription factors control the expression of genes up regulated by either TNF or PACAP . Most of the genes up regulated by TNF contained response elements for members of the Rel transcription factor family, suggesting TNF-TNFR2 signaling mainly through the NF-kB signaling pathway. On the other hand, the PACAP regulated genes showed no enrichment for any single response element, containing instead response elements for combinations of transcription factors allowing activation through multiple signaling pathways, including cAMP, calcium and ERK, in neuroendocrine cells. Pharmacological strategies for mimicking neuroprotection by either PACAP or TNF in the context of CNS injury or degeneration in disease might focus on individual downstream gene activation pathways to achieve greater specificity in vivo. For our analysis we have used both Affymetrix and Agilent arrays to identify the genes that are regulated up or down by neuropeptide PACAP and TNF-alpha. On Affyemetrix platform we performed technical repeats with 3 arrays with untreated samples, 3 arrays with samples from PACAP treatment, and 3 array with samples from TNF-alpha treatment. On the Agilent platform we performed technical repeats with 3 arrays for each treatment hybridizing Cy3-labelled RNA from untreated samples and Cy5-labelled RNA from either TNF-alpha or PACAP treated samples.

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Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Promotes Regeneration of Corneal Epithelial Cells via NR4A1 Signaling Pathway

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