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

2021; Lippincott Williams & Wilkins; Volume: 207; Issue: 3 Linguagem: Inglês

10.1097/ju.0000000000002278

1527-3792

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

Urinary and Genital Oncology Studies

No AccessJournal of UrologyAdult Urology1 Mar 2022Overexpression of HIF1α in Hunner Lesions of Interstitial Cystitis: Pathophysiological ImplicationsThis article is commented on by the following:Editorial CommentEditorial Comment Yoshiyuki Akiyama, Jimpei Miyakawa, Michael A. O’Donnell, Karl J. Kreder, Yi Luo, Daichi Maeda, Tetsuo Ushiku, Haruki Kume, and Yukio Homma Yoshiyuki AkiyamaYoshiyuki Akiyama *Correspondence: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan telephone: +81-35-800-8753 [03-5800-8753]; FAX: +81-35-800-6435 [03-5800-6435]; E-mail Address: [email protected] http://orcid.org/0000-0003-1439-5640 Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan More articles by this author , Jimpei MiyakawaJimpei Miyakawa Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan More articles by this author , Michael A. O’DonnellMichael A. O’Donnell Department of Urology, University of Iowa, Iowa City, Iowa More articles by this author , Karl J. KrederKarl J. Kreder Department of Urology, University of Iowa, Iowa City, Iowa More articles by this author , Yi LuoYi Luo Department of Urology, University of Iowa, Iowa City, Iowa More articles by this author , Daichi MaedaDaichi Maeda Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan More articles by this author , Tetsuo UshikuTetsuo Ushiku Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan More articles by this author , Haruki KumeHaruki Kume Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan More articles by this author , and Yukio HommaYukio Homma Japanese Red Cross Medical Center, Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002278AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: The aim of our study was 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, 1 sample each from the Hunner lesion and nonlesion 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 nonlesion areas. Results: RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (24) included HIF1α signaling pathway, PI3K-Akt signaling pathway, RAS signaling pathway and MAPK signaling pathway. By contrast, down-regulated pathways (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 nonlesion 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. References 1. : Clinical guidelines for interstitial cystitis/bladder pain syndrome. Int J Urol 2020; 27: 578. Google Scholar 2. : Phenotyping of interstitial cystitis/bladder pain syndrome. Int J Urol, suppl., 2019; 26: 17. 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Performed the experiments: YA, JM. Analyzed the data: YA, JM. Wrote the paper: YA. Interpreted the data: YA, YL, MAO, KJK, YH. Revised the manuscript critically: YL, DM, MAO, KJK, TU, HK, YH. Final approval of the version to be published: YA, YL, MAO, KJK, YH. Competing interests: The authors have no relevant financial interests to disclose. © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyDec 8, 2021, 12:00:00 AMEditorial CommentJournal of UrologyDec 8, 2021, 12:00:00 AMEditorial Comment Volume 207Issue 3March 2022Page: 635-646Supplementary Materials Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.Keywordshypoxia-inducible factor 1, alpha subunitcystitis, interstitialRNA-seqAcknowledgmentsWe thank Kei Sakuma for technical support in immunohistochemistry.MetricsAuthor Information Yoshiyuki Akiyama Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan *Correspondence: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan telephone: +81-35-800-8753 [03-5800-8753]; FAX: +81-35-800-6435 [03-5800-6435]; E-mail Address: [email protected] More articles by this author Jimpei Miyakawa Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan More articles by this author Michael A. O’Donnell Department of Urology, University of Iowa, Iowa City, Iowa More articles by this author Karl J. Kreder Department of Urology, University of Iowa, Iowa City, Iowa More articles by this author Yi Luo Department of Urology, University of Iowa, Iowa City, Iowa More articles by this author Daichi Maeda Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan More articles by this author Tetsuo Ushiku Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan More articles by this author Haruki Kume Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan More articles by this author Yukio Homma Japanese Red Cross Medical Center, Tokyo, Japan More articles by this author Expand All Support: This study was financially supported by the KAKENHI Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) [grant number 17H06639] (to YA). Author contributions: Conceived and designed the experiments: YA. Performed the experiments: YA, JM. Analyzed the data: YA, JM. Wrote the paper: YA. Interpreted the data: YA, YL, MAO, KJK, YH. Revised the manuscript critically: YL, DM, MAO, KJK, TU, HK, YH. Final approval of the version to be published: YA, YL, MAO, KJK, YH. Competing interests: The authors have no relevant financial interests to disclose. Advertisement PDF DownloadLoading ...