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The discovery of new therapies heavily depends on understanding key signalling pathways that lead to ADPKD. The <jats:underline>JA<\/jats:underline>nus <jats:underline>K<\/jats:underline>inase and <jats:underline>S<\/jats:underline>ignal <jats:underline>T<\/jats:underline>ransducers and <jats:underline>A<\/jats:underline>ctivators of <jats:underline>T<\/jats:underline>ranscription (JAK\/STAT) pathway is aberrantly activated and contributes to ADPKD\u00a0pathogenesis via enhancing epithelial proliferation. Yet the mechanisms underlying the upregulation of JAK\/STAT activity in\u00a0this disease context is completely unknown. Here, we investigate the role of JAK2\u00a0in ADPKD using\u00a0a murine model of ADPKD (Pkd1<jats:sup>nl\/nl<\/jats:sup>). In normal kidneys, JAK2 expression is limited to tubular epithelial and vascular cells with lesser staining in bowman\u2019s 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\u00a0ectopically 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 <jats:italic>Tofacitinib<\/jats:italic>, 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.<\/jats:p>","DOI":"10.1038\/s41598-019-41106-3","type":"journal-article","created":{"date-parts":[[2019,3,14]],"date-time":"2019-03-14T12:06:06Z","timestamp":1552565166000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis"],"prefix":"10.1038","volume":"9","author":[{"given":"Foteini","family":"Patera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Cudzich-Madry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Fragiadaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,14]]},"reference":[{"key":"41106_CR1","doi-asserted-by":"publisher","first-page":"2458","DOI":"10.1093\/ndt\/gfp136","volume":"24","author":"PJ Azurmendi","year":"2009","unstructured":"Azurmendi, P. J. et al. Early renal and vascular changes in ADPKD patients with low-grade albumin excretion and normal renal function. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 24, 2458\u20132463, https:\/\/doi.org\/10.1093\/ndt\/gfp136 (2009).","journal-title":"Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association"},{"key":"41106_CR2","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1038\/nrneph.2013.214","volume":"9","author":"EF Carney","year":"2013","unstructured":"Carney, E. F. Polycystic kidney disease: TGF-beta signalling and vascular complications in ADPKD. 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Pharmacokinetics and Pharmacodynamics of Curcumin in regulating anti-inflammatory and epigenetic gene expression. Biopharm Drug Dispos. https:\/\/doi.org\/10.1002\/bdd.2136 (2018).","journal-title":"Biopharm Drug Dispos"},{"key":"41106_CR6","doi-asserted-by":"publisher","first-page":"F1193","DOI":"10.1152\/ajprenal.00419.2010","volume":"300","author":"WN Leonhard","year":"2011","unstructured":"Leonhard, W. N. et al. Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1-deletion model. American journal of physiology. Renal physiology 300, F1193\u20131202, https:\/\/doi.org\/10.1152\/ajprenal.00419.2010 (2011).","journal-title":"American journal of physiology. Renal physiology"},{"key":"41106_CR7","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.kint.2016.10.039","volume":"91","author":"M Fragiadaki","year":"2017","unstructured":"Fragiadaki, M. et al. STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease. Kidney international 91, 575\u2013586, https:\/\/doi.org\/10.1016\/j.kint.2016.10.039 (2017).","journal-title":"Kidney international"},{"key":"41106_CR8","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0092-8674(02)00716-X","volume":"109","author":"AK Bhunia","year":"2002","unstructured":"Bhunia, A. K. et al. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109, 157\u2013168 (2002).","journal-title":"Cell"},{"key":"41106_CR9","doi-asserted-by":"publisher","first-page":"7985","DOI":"10.1073\/pnas.1103816108","volume":"108","author":"JJ Talbot","year":"2011","unstructured":"Talbot, J. J. et al. Polycystin-1 regulates STAT activity by a dual mechanism. 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