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

Purpose To elucidate biological changes in Hunner lesions, which underlie the pathophysiology of Hunner-type interstitial cystitis, by characterizing their whole transcriptome and immunopathological profiles. Materials and methods 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. Results RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (N=24) included 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 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. Conclusions 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.