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3 in Renal Tubulointerstitial Fibrosis Ying Targeting receptor-interacting serine/threonine- protein kinase (RIPK)3 in renal tubulointerstitial fibrosis Ying Shi A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Sydney Medical School The University of Sydney 2019 Statement of originality This thesis is submitted to The University of Sydney in fulfilment of the requirement for the degree of Doctor of Philosophy. This is to certify that to the best of my knowledge and belief, the content of this thesis is my own work and that all the assistance received in preparing this thesis and sources have been acknowledged. This thesis has not been submitted for any degree or other purposes. Ying Shi 1 Abstract Chronic kidney disease (CKD) affects almost 10% of the adult population worldwide. Regardless of the initial cause of renal injury, renal fibrosis is the final common pathway of all forms of CKD, including diabetic kidney disease (DKD). However, current therapies to attenuate the development of progressive renal fibrosis are limited to blockade of the renin- angiotensin-aldosterone system (RAAS), achievement of blood pressure targets and in the case of DKD, blood glucose control. More recently inhibition of sodium-glucose linked transporter-2 has shown impressive renoprotective benefits in secondary analyses of major cardiovascular end-point trials. However, studies, where renal disease is a primary endpoint, are awaited. Given the personal and societal impacts of the increasing burden of CKD, it is of utmost importance to identify novel interventions for preventing the progressive renal fibrosis and thus progressive CKD. Receptor-interacting serine/threonine-protein kinase (RIPK) 3, known as a necroptotic kinase, is recognised to be involved in various innate immune responses, including necroptosis and activation of the toll-like receptor (TLR) 2 and 4 pathways and the pyrin domain-containing protein (NLRP) 3 inflammasome. However, the role of RIPK3 in the development of renal cortical fibrosis, and in particular in the pathology observed in the renal tubule under conditions that stimulate a fibrotic response has not been elucidated. In this thesis, mouse models of folic acid (FA)-induced nephropathy (studied at 28 days) and streptozotocin (STZ)-induced diabetic nephropathy (studied at 24 weeks) were developed. RIPK3 knock out (KO) mice were used to determine the therapeutic effect of RIPK3 in renal fibrosis, and the RIPK3 inhibitor dabrafenib was utilized as a pharmacological inhibitor of RIPK3. Human proximal tubular cells exposed to transforming growth factor beta-β1 (TGF- II β1) were used as in vitro model to determine the role of necroptosis in the development of tubular pathology under pro-fibrotic influences. Inflammatory and fibrotic markers, as well as the relevant signalling pathways, were examined. Our results show that blockade of RIPK3 genetically or pharmacologically suppressed FA- induced activation of the TLR2 and 4 pathways, the NLRP3 inflammasome and TGF-β1 expression, associated with a reduced myofibroblast activation and interstitial extracellular matrix (ECM) deposition. RIPK3 inhibition also confers renoprotection in the STZ-induced diabetic nephropathy model. A reduction of TGF-β1, NLRP3 activation and TLR4 but not TLR2 was observed in RIPK3 KO mice. Inhibition of necroptosis also reduced TGF-β1 and ECM secretion in tubular cells exposed to TGF-β1. Collectively, the data shown in the thesis uniquely demonstrate that RIPK3 is involved in the development of renal fibrosis via multiple pathways, including necroptosis, TLR2 and 4 signalling and activation of the NLRP3 inflammasome. Given the two strategies to inhibit RIPK3 converge on inhibition of the TLR4 pathway and the NLRP3 inflammasome activation, we consider these are key pathways to inhibit to confer renoprotection. Dabrafenib, the RIPK3 inhibitor, deserves further exploration for repurposing as a targeted renal therapy. III Acknowledgement It would not have been possible to finish this doctoral thesis without the guidance and kind support from my supervisors, help from friends, and endless amounts of love from my parents. Here I would like to express my deepest appreciation to all those who provide me with the possibility to complete this thesis. First and foremost, my thanks go to my supervisor Professor Carol Pollock for her guidance, absolute support throughout my studies. I have been extremely lucky to have a supervisor who was so supportive and cared so much about my work, and who responded to my questions and queries so promptly. She is truly an inspirational mentor and it has been an enormous privilege to work under the supervision of such an exceptional person. My co-supervisor A/Professor Xinming has been a long-standing mentor and provided unfailing support during the three years of study. Thanks for always being available when I needed help and sharing a lot of science and knowledge with me. I would like to express my sincere gratitude to my co-supervisor Dr Chunling Huang for her constant source of guidance and emotional support throughout. Thank you for all your words of advice and for sharing your knowledge. IV I would like to thank Dr Jason Chen for being so kind in helping me with the processing of animal tissues and subsequent analysis. I must express my gratitude to my parents for their continued support and encouragement. I was, and still am, continually amazed by their patience and willingness to listen to the minutiae of my project and day-to-day laboratory work and for being on my journey of the ups and downs of research. I am grateful for their support in all my decisions. I would like to thank A/Professor Usha Panchapakesan, Dr Sonia Saad and Dr Muh Geot for their technical expertise, invaluable advice and kind encouragement. To all my colleagues at the Kolling Institute within the Renal Laboratory group including Long, Hao, Sanela, Jessica, Amgad, Ben, Sarah and Stephanie, thanks for your friendship and for always being there when I needed help and emotional support. Especially thanks to Hao and Long for ordering reagents. To many other colleagues and friends at the Kolling Institute, including Grace, Lauren, Jingting thanks for making the institute a very friendly place. Special thanks to Martyn for advice required during my experimental troubleshooting and kindly sharing his experience and protocols. I would like to thank for Royal North Shore Hospital and Professor Carol Pollock and the China Scholarship Council for Postgraduate Research Scholarship support. V Publications 1. Huang, C., L. Zhang, Y. Shi, H. Yi, Y. Zhao, J. Chen, C. A. Pollock and X. M. Chen (2018). "The KCa3.1 blocker TRAM34 reverses renal damage in a mouse model of established diabetic nephropathy." PLoS One 13(2): e0192800. (not directly the subject of my thesis but I acquired skills relevant to my project by virtue of contribution to this work) 2. Yi, H., C. Huang, Y. Shi, Q. Cao, Y. Zhao, L. Zhang, J. Chen, C. A. Pollock and X. M. Chen (2018). "Metformin attenuates folic-acid induced renal fibrosis in mice." J Cell Physiol an 30. doi: 10.1002/jcp.26505. (not directly the subject of my thesis but I acquired skills relevant to my project by virtue of contribution to this work) Manuscripts in preparation 1. Ying Shi, Chunling Huang, Yongli Zhao, Jason Chen, Hao Yi, Qinghua Cao, Carol Pollock, Xinming Chen - RIPK3 blockade attenuates kidney fibrosis in a folic acid model of renal injury. 2. Ying Shi, Chunling Huang, Yongli Zhao, Hao Yi, Qinghua Cao, Carol Pollock, Xinming Chen - RIPK3 blockade attenuates tubulointerstitial fibrosis in a mouse model of diabetic nephropathy. VI Presentations arising from this work • RIPK1: the next novel target for renal fibrosis, Oral presentation, 15th Asian Pacific Conference of Nephrology (APCN) 2016, Perth, Australia, September 17-21, 2016. • RIPK1: the next novel target for renal fibrosis, Oral presentation, New Horizons 2016 Conference, Sydney, Australia, November 21-22, 2016. • Blockade of RIPK3 attenuates folic acid-induced kidney fibrosis of C57BL/6 mouse, Young Investigator Award Oral presentation, Annual Scientific Meeting of Australian and New Zealand Society of Nephrology, Darwin, Australia, September 4-6, 2017 • RIPK1 inhibition alleviates renal fibrogenesis, Oral presentation, Annual Scientific Meeting of Australian and New Zealand Society of Nephrology, Darwin, Australia, September 4-6, 2017 • RIPK3 inhibition alleviates folic acid-induced kidney fibrosis of C57BL/6 mouse, Poster presentation, American Society of Nephrology Kidney Week, New Orleans, America, October 31 - November 5, 2017 • RIPK3 blockade ameliorates renal fibrosis in diabetic model of eNOS knockout mice, Poster presentation, American Society of Nephrology Kidney Week, New Orleans, America, October 31 - November 5, 2017 • RIPK3 inhibition alleviates folic acid-induced kidney fibrosis of C57BL/6 mouse, Oral presentation, 16th Asian Pacific Congress of Nephrology (APCN), Beijing, China, March 27-31, 2018 • Blockade of RIPK3 alleviates renal fibrogenesis trough NLRP3 inflammasome in folic acid induced kidney fibrosis model, Oral presentation, Annual Scientific Meeting of Australian and New Zealand Society of Nephrology, Sydney, Australia, September 10-12, 2018 VII Awards arising from this work • Postgraduate Research Support Scheme (PRSS) 2015 • Postgraduate Research Support Scheme (PRSS) 2016 • Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology (ANZSN) 2017 Young Investigator Award finalist • Scientific Staff
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