{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:11:31Z","timestamp":1773871891506,"version":"3.50.1"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T00:00:00Z","timestamp":1569801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T00:00:00Z","timestamp":1569801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic Kidney Disease is a growing problem across the world and can lead to end-stage kidney disease and cardiovascular disease. Fibrosis is the underlying mechanism that leads to organ dysfunction, but as yet we have no therapeutics that can influence this process. Ras monomeric GTPases are master regulators that direct many of the cytokines known to drive fibrosis to downstream effector cascades. We have previously shown that K-Ras is a key isoform that drives fibrosis in the kidney. Here we demonstrate that K-Ras expression and activation are increased in rodent models of CKD. By knocking down expression of K-Ras using antisense oligonucleotides in a mouse model of chronic folic acid nephropathy we can reduce fibrosis by 50% and prevent the loss of renal function over 3 months. In addition, we have demonstrated <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> that reduction of K-Ras expression is associated with a reduction in Jag1 expression; we hypothesise this is the mechanism by which targeting K-Ras has therapeutic benefit. In conclusion, targeting K-Ras expression with antisense oligonucleotides in a mouse model of CKD prevents fibrosis and protects against renal dysfunction.<\/jats:p>","DOI":"10.1038\/s41598-019-50422-7","type":"journal-article","created":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T10:04:48Z","timestamp":1569837888000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Inhibition of Kirsten-Ras reduces fibrosis and protects against renal dysfunction in a mouse model of chronic folic acid nephropathy"],"prefix":"10.1038","volume":"9","author":[{"given":"Lucy J.","family":"Newbury","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jui-Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gene","family":"Hung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7950-7685","authenticated-orcid":false,"given":"Bruce M.","family":"Hendry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1704-8492","authenticated-orcid":false,"given":"Claire C.","family":"Sharpe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"50422_CR1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0140-6736(14)61682-2","volume":"385","author":"Mortality GBD, Causes of Death C","year":"2015","unstructured":"Mortality GBD, Causes of Death C. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990\u20132013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385, 117\u2013171 (2015).","journal-title":"Lancet"},{"key":"50422_CR2","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/sj.ki.5000054","volume":"69","author":"Y Liu","year":"2006","unstructured":"Liu, Y. Renal fibrosis: New insights into the pathogenesis and therapeutics. Kidney Int 69, 213\u2013217 (2006).","journal-title":"Kidney Int"},{"key":"50422_CR3","doi-asserted-by":"crossref","unstructured":"Liu, F. & Zhuang, S. Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis. Int J Mol Sci 17 (2016).","DOI":"10.3390\/ijms17060972"},{"key":"50422_CR4","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/nrc1097","volume":"3","author":"M Malumbres","year":"2003","unstructured":"Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nat Rev Cancer 3, 459\u2013465 (2003).","journal-title":"Nat Rev Cancer"},{"issue":"3","key":"50422_CR5","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1159\/000221834","volume":"112","author":"ME Dockrell","year":"2009","unstructured":"Dockrell, M. E., Phanish, M. K. & Hendry, B. M. TGF-beta auto-induction and CTGF expression in human renal tubule epithelial cells requires N-ras. Nephron Exp Nephrol. 112(3), 71\u20139 (2009).","journal-title":"Nephron Exp Nephrol."},{"key":"50422_CR6","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1093\/cvr\/cvr067","volume":"91","author":"L Li","year":"2011","unstructured":"Li, L. et al. Angiotensin II increases periostin expression via Ras\/p38 MAPK\/CREB and ERK1\/2\/TGF-beta1 pathways in cardiac fibroblasts. Cardiovasc Res 91, 80\u201389 (2011).","journal-title":"Cardiovasc Res"},{"key":"50422_CR7","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.yexcr.2007.09.001","volume":"314","author":"GA Secker","year":"2008","unstructured":"Secker, G. A. et al. TGFbeta stimulated re-epithelialisation is regulated by CTGF and Ras\/MEK\/ERK signaling. Exp Cell Res 314, 131\u2013142 (2008).","journal-title":"Exp Cell Res"},{"key":"50422_CR8","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1681\/ASN.V1191600","volume":"11","author":"CC Sharpe","year":"2000","unstructured":"Sharpe, C. C. et al. Role of Ras isoforms in the stimulated proliferation of human renal fibroblasts in primary culture. J Am Soc Nephrol 11, 1600\u20131606 (2000).","journal-title":"J Am Soc Nephrol"},{"key":"50422_CR9","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.ajpath.2011.09.036","volume":"180","author":"JH Wang","year":"2012","unstructured":"Wang, J. H. et al. Antisense knockdown of KRas inhibits fibrosis in a rat model of unilateral ureteric obstruction. The American Journal of Pathology 180, 82\u201390 (2012).","journal-title":"The American Journal of Pathology"},{"key":"50422_CR10","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/nm.2135","volume":"16","author":"W Bechtel","year":"2010","unstructured":"Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16, 544\u2013550 (2010).","journal-title":"Nat Med"},{"key":"50422_CR11","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/S0015-6264(73)80494-8","volume":"11","author":"CE Searle","year":"1973","unstructured":"Searle, C. E. & Blair, J. A. The renal toxicity of folic acid in mice. Food Cosmet Toxicol 11, 277\u2013281 (1973).","journal-title":"Food Cosmet Toxicol"},{"key":"50422_CR12","doi-asserted-by":"publisher","first-page":"4040","DOI":"10.1172\/JCI43025","volume":"120","author":"B Bielesz","year":"2010","unstructured":"Bielesz, B. et al. Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J Clin Invest 120, 4040\u20134054 (2010).","journal-title":"J Clin Invest"},{"issue":"6","key":"50422_CR13","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/ki.2009.498","volume":"77","author":"M. Teresa Grande","year":"2010","unstructured":"Grande, M. T. et al. Deletion of H-Ras decreases renal fibrosis and myofibroblast activation following ureteral obstruction in mice. Kidney Int. 77(6):509\u201318 (2010 Mar).","journal-title":"Kidney International"},{"issue":"12","key":"50422_CR14","doi-asserted-by":"publisher","first-page":"2734","DOI":"10.1016\/j.bbamcr.2013.07.008","volume":"1833","author":"Isabel Fuentes-Calvo","year":"2013","unstructured":"Fuentes-Calvo, I., Crespo, P., Santos, E., L\u00f3pez-Novoa, J. M., Mart\u00ednez-Salgado, C. The small GTPase N-Ras regulates extracellular matrix synthesis, proliferation and migration in fibroblasts. Biochim Biophys Acta. 1833(12):2734\u20132744 (2013 Dec).","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"50422_CR15","doi-asserted-by":"crossref","unstructured":"Kano, Y. et al. New structural and functional insight into the regulation of Ras. Semin Cell Dev Biol (2016).","DOI":"10.1016\/j.semcdb.2016.06.006"},{"key":"50422_CR16","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1002\/1873-3468.12158","volume":"590","author":"X Xu","year":"2016","unstructured":"Xu, X. et al. Hypoxia-induced endothelial-mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells. FEBS Lett 590, 1222\u20131233 (2016).","journal-title":"FEBS Lett"},{"key":"50422_CR17","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1093\/cvr\/cvv015","volume":"105","author":"X Xu","year":"2015","unstructured":"Xu, X. et al. Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis. Cardiovasc Res 105, 279\u2013291 (2015).","journal-title":"Cardiovasc Res"},{"key":"50422_CR18","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/164_2015_28","volume":"232","author":"S Knapp","year":"2016","unstructured":"Knapp, S. Emerging Target Families: Intractable Targets. Handb Exp Pharmacol 232, 43\u201358 (2016).","journal-title":"Handb Exp Pharmacol"},{"key":"50422_CR19","first-page":"932","volume":"45","author":"H Sands","year":"1994","unstructured":"Sands, H. et al. Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate. Mol Pharmacol 45, 932\u2013943 (1994).","journal-title":"Mol Pharmacol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50422-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50422-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50422-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T14:01:45Z","timestamp":1671285705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50422-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,30]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["50422"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-50422-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,30]]},"assertion":[{"value":"4 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"G.H. is an employee and stock holder of Ionis Pharmaceuticals. BMH has received compensation as speaker fees from Gilead Sciences, Otsuka Pharmaceuticals, Sanofi and Viiv Pharmaceuticals.\u00a0C.C.S. has received compensation as a member of a scientific advisory board for Novartis Pharmaceuticals. L.N. and J.-H.W. have no competing interests, financial or otherwise.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14010"}}