Patera, F., Cudzich-Madry, A., Huang, Z. et al. (1 more author) (2019) Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis. Scientific Reports, 9. 4491. ISSN 2045-2322
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal genetic disorder, however it still lacks a cure. The discovery of new therapies heavily depends on understanding key signalling pathways that lead to ADPKD. The JAnus Kinase and Signal Transducers and Activators of Transcription (JAK/STAT) pathway is aberrantly activated and contributes to ADPKD pathogenesis via enhancing epithelial proliferation. Yet the mechanisms underlying the upregulation of JAK/STAT activity in this disease context is completely unknown. Here, we investigate the role of JAK2 in ADPKD using a murine model of ADPKD (Pkd1nl/nl). In normal kidneys, JAK2 expression is limited to tubular epithelial and vascular cells with lesser staining in bowman's capsule and remains below detection level in the interstitium. By contrast, in kidneys of mice with ADPKD, JAK2 is higher in cyst-lining cells when compared to normal tubules and critically, it is ectopically expressed in the interstitium, suggesting that ectopic JAK2 may contribute to ADPKD. JAK2 activity was inhibited using either curcumin, a natural compound with strong JAK2 inhibitor activity, or Tofacitinib, a clinically used selective JAK small molecule inhibitor. JAK2 inhibition led to significantly reduced tyrosine phosphorylation of STAT3 and markedly reduced cystic growth of human and mouse ADPKD-derived cells in cystogenesis assays. Taken together, our results indicate that blockade of JAK2 shows promise as a novel therapeutic target in ADPKD.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 22 Mar 2019 12:14 |
Last Modified: | 22 Mar 2019 12:14 |
Status: | Published |
Publisher: | Nature Research (part of Springer Nature |
Refereed: | Yes |
Identification Number: | 10.1038/s41598-019-41106-3 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:143818 |