Overexpression of HIF1α in Hunner Lesions of Interstitial Cystitis: Pathophysiological Implications.

To elucidate biological changes in Hunner lesions, which underlie the pathophysiology of Hunner-type interstitial cystitis, by characterizing their whole transcriptome and immunopathological profiles.

Paired bladder mucosal biopsies, one sample each from the Hunner lesion and non-lesion area, were obtained from 25 patients with Hunner-type interstitial cystitis. The samples were subjected to whole-transcriptome profiling; immunohistochemical quantification of CD3, CD4, CD8, CD20, CD138, mast cell tryptase, cytokeratin, and HIF1α; and quantitative polymerase chain reaction for IFN-α, IFN-β, IFN-γ, TNF, TGF-β1, HIF1α, IL-2, IL-4, IL-6, IL-10, and IL-12A. The results were compared between the lesion and non-lesion areas.

RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (N=24) included "HIF1α signaling pathway", "PI3K-Akt signaling pathway", "RAS signaling pathway", and "MAPK signaling pathway." By contrast, down-regulated pathways (N=6) included "basal cell carcinoma" and "protein digestion and absorption". The mRNA levels of HIF1α, IFN-γ, and IL-2 and the HIF1α protein level were significantly higher in lesion areas. Otherwise, there were no significant differences between the lesion and non-lesion samples in terms of mRNA levels of inflammatory cytokines or histological features such as lymphoplasmacytic and mast cell infiltration, epithelial denudation, and CD4/CD8 T-lymphocyte ratio.

Our findings demonstrate significant overexpression of HIF1α and up-regulation of its related biological pathways in Hunner lesions. The results indicate that ischemia, in conjunction with inflammation, plays a pathophysiological role in this subtype of interstitial cystitis/bladder pain syndrome, particularly in Hunner lesions.

The Journal of urology. 2021 Oct 25 [Epub ahead of print]

Yoshiyuki Akiyama, Jimpei Miyakawa, Michael A O'Donnell, Karl J Kreder, Yi Luo, Daichi Maeda, Tetsuo Ushiku, Haruki Kume, Yukio Homma

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Department of Urology, University of Iowa, Iowa City, Iowa., Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan., Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Japanese Red Cross Medical Center, Tokyo, Japan.

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