STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

Abstract

Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signalling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here we present an siRNA JAK-STAT focused screen revealing a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, STAT5b). Amongst these we selected to study the GH-GHR-STAT5-axis because of its known role as a regulator of growth in non-renal tissues. We show that STAT5 loss of function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth in vitro. To study whether STAT5 is abnormally activated in vivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both. To test whether forced activation of STAT5 can modulate proliferation of renal cells in vivo, irrespective of Pkd1 status, we overexpressed growth hormone (GH). GH mice showed increased STAT5 activity in renal epithelial cells, correlating with de-novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitations, revealed that STAT5 transcriptionally activated cyclin D1 in GH-stimulated renal epithelial but not control cells, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated GH in Pkd1 nl/nl mice. Collectively, our data identify the GH-STAT5 signalling axis as a novel therapeutic target in ADPKD.

JAK2 is highly expressed by cyst-lining cells and regulates cystogenesis

“…JAK-STAT is an evolutionarily conserved pathway misregulated in a number of conditions such as cancer, arthritis and other inflammatory diseases 4 . We, and others, have previously shown that this pathway is abnormally activated in, and contributes to, ADPKD 5-9 . The pathway becomes activated by a series of tyrosine phosphorylation steps mediated by one of the four kinases JAK1-JAK3 or Tyk2.…”

Ankhd1enhances polycystic kidney disease development via promoting proliferation and fibrosis

“…Mechanistically we identify that ANKHD1 alters proliferative signalling by enhancing STAT5-driven transcription in ADPKD kidneys. This is interesting since it was recently shown that STAT5 is a major contributor to proliferation and ADPKD disease progression 18 . The fact that ANKHD1 drives proliferation and enhances fibrogenesis together suggest that it is an ideal future therapeutic target, since its successful inhibition is predicted to block both the growth of cysts and inhibit tissue scarring, which is a final common pathway to organ failure irrespective of the initial cause of damage.…”

“…ANKHD1 enhances ADPKD proliferation by promoting STAT5 signalling. It was previously reported that ADPKD is characterised by altered JAK/STAT signalling and specifically STAT5 is elevated in polycystic kidneys 18 . Our previous RNA-seq data illustrated that ANKHD1 alters JAK/STAT activity, therefore, to investigate a potential role of Ankhd1 in the control of STAT5 signalling, we used mice with targeted Ankhd1deficiency in the Pkd1 nl/nl model of polycystic kidney disease.…”

“…ANKHD1 has a classic RNA binding domain (KH) and is involved in proliferative signalling in Drosophila, by enhancing for example JAK/STAT, HIPPO and EGF/MAP pathway activities [11][12][13][14] . Interestingly all of aforementioned signalling pathways are dysregulated and drive ADPKD development [15][16][17][18] . Moreover, ANKHD1 enhances renal cancer cell growth 19 .…”

“…The Drosophila homologue of ANKHD1, MASK, enhances JAK/STAT, HIPPO and EGF/MAP 11-14 pathway activity. Interestingly all of these proliferative pathways are dysregulated and contribute to ADPKD development [15][16][17][18] . Yet, the role of ANKHD1 ADPKD progression is unknown.…”