{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:25:46Z","timestamp":1787761546117,"version":"build-2784847793"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,5,30]],"date-time":"2021-05-30T00:00:00Z","timestamp":1622332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["MOST 105-2314-B-037-043-MY3"],"award-info":[{"award-number":["MOST 105-2314-B-037-043-MY3"]}]},{"name":"Ministry of Science and Technology","award":["MOST109-2314-B-037-096"],"award-info":[{"award-number":["MOST109-2314-B-037-096"]}]},{"name":"Kaohsiung Medical University Hospital","award":["KMUH-106-6R60"],"award-info":[{"award-number":["KMUH-106-6R60"]}]},{"name":"Kaohsiung Municipal Ta-Tung Hospital","award":["KMTTH-108-002"],"award-info":[{"award-number":["KMTTH-108-002"]}]},{"name":"Kaohsiung Municipal Ta-Tung Hospital","award":["KMTTH-108-003"],"award-info":[{"award-number":["KMTTH-108-003"]}]},{"name":"Ministry of Health and Welfare","award":["MOHW107-TDU-B-212-123006"],"award-info":[{"award-number":["MOHW107-TDU-B-212-123006"]}]},{"name":"Ministry of Health and Welfare","award":["MOHW108-TDU-B-212-133006"],"award-info":[{"award-number":["MOHW108-TDU-B-212-133006"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Biology"],"abstract":"<jats:p>The present study attempts to elucidate whether autophagy alters bladder angiogenesis, decreases inflammatory response, and ameliorates bladder hyperactivity\u2014thereby influencing bladder function in ketamine-induced cystitis (KIC). In our methodology, female Sprague-Dawley (S-D) rats were randomly divided into the control group, the ketamine group, the ketamine+rapamycin group, and the ketamine+wortmannin group. The bladder function, contractile activity of detrusor smooth muscle, distribution of autophagosome and autolysosome, total white blood cells (WBCs) and leukocyte differential counts, the expressions of autophagy-associated protein, angiogenesis markers, and signaling pathway molecules involved in KIC were tested, respectively. The data revealed that treatment with ketamine significantly results in bladder overactivity, enhanced interstitial fibrosis, impaired endothelium, induced eosinophil-mediated inflammation, swelling, and degraded mitochondria and organelles, inhibited angiogenesis, and elevated the phosphorylation of Akt. However, treatment with rapamycin caused an inhibitory effect on vascular formation, removed ketamine metabolites, decreased the eosinophil-mediated inflammation, and ameliorated bladder hyperactivity, leading to improve bladder function in KIC. Moreover, wortmannin treatment reduced basophil-mediated inflammatory response, improved bladder angiogenesis by increasing capillary density and VEGF expression, to reverse antiangiogenic effect to repair KIC. In conclusion, these findings suggested that autophagy could modulate inflammatory responses and angiogenesis, which improved bladder function in KIC.<\/jats:p>","DOI":"10.3390\/biology10060488","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:22:15Z","timestamp":1622420535000},"page":"488","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Autophagy Alters Bladder Angiogenesis and Improves Bladder Hyperactivity in the Pathogenesis of Ketamine-Induced Cystitis in a Rat Model"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9108-7567","authenticated-orcid":false,"given":"Jian-He","family":"Lu","sequence":"first","affiliation":[{"name":"Emerging Compounds Research Center, Department of Environmental Science and Engineering, College of Engineering, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2366-8268","authenticated-orcid":false,"given":"Yi-Hsuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Jui","family":"Juan","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Defense Medical College, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, I-Shou University, Kaohsiung 84001, Taiwan"},{"name":"Division of Urology, Department of Surgery, E-Da Cancer Hospital, Kaohsiung 82445, Taiwan"},{"name":"Division of Urology, Department of Surgery, E-Da Hospital, Kaohsiung 82445, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong-Jyh","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Parasitology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuang-Shun","family":"Chueh","sequence":"additional","affiliation":[{"name":"Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80661, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chen","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Yuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Shun","family":"Juan","sequence":"additional","affiliation":[{"name":"Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80661, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1111\/j.1464-410X.2008.07920.x","article-title":"The destruction of the lower urinary tract by ketamine abuse: A new syndrome?","volume":"102","author":"Chu","year":"2008","journal-title":"BJU Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/1752-1947-2-219","article-title":"Cystitis due to the use of ketamine as a recreational drug: A case report","volume":"2","author":"Colebunders","year":"2008","journal-title":"J. Med. Case Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1007\/s00280-010-1392-z","article-title":"Cyclooxygenase-2 contributes to functional changes seen on experimental hemorrhagic cystitis induced by ifosfamide in rat urinary bladder","volume":"67","author":"Macedo","year":"2011","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1136\/postgradmedj-2013-131776","article-title":"Evaluation of the extent of ketamine-induced uropathy: The role of CT urography","volume":"90","author":"Huang","year":"2014","journal-title":"Postgrad. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/ki.2011.242","article-title":"\u2018Walking-stick ureters\u2019 in ketamine abuse","volume":"80","author":"Huang","year":"2011","journal-title":"Kidney Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/j.juro.2014.05.084","article-title":"Elevated serum IgE may be associated with development of ketamine cystitis","volume":"192","author":"Jhang","year":"2014","journal-title":"J. Urol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1111\/bju.12256","article-title":"Increased apoptosis and suburothelial inflammation in patients with ketamine-related cystitis: A comparison with non-ulcerative interstitial cystitis and controls","volume":"112","author":"Lee","year":"2013","journal-title":"BJU Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1111\/iju.12841","article-title":"Possible pathophysiology of ketamine-related cystitis and associated treatment strategies","volume":"22","author":"Jhang","year":"2015","journal-title":"Int. J. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1038\/s41467-020-18167-4","article-title":"Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology","volume":"11","author":"Chen","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signaling","volume":"1","author":"Berridge","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1080\/15548627.2017.1384887","article-title":"Ion channels in the regulation of autophagy","volume":"14","author":"Kondratskyi","year":"2018","journal-title":"Autophagy"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Li, M., Gao, P., and Zhang, J. (2016). Crosstalk between Autophagy and Apoptosis: Potential and Emerging Therapeutic Targets for Cardiac Diseases. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030332"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bonam, S.R., Bayry, J., and Mario PTschan Muller, S. (2020). Progress and Challenges in the Use of MAP1LC3 as a Legitimate Marker for Measuring Dynamic Autophagy In Vivo. Cells, 9.","DOI":"10.3390\/cells9051321"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.1016\/j.bbamcr.2013.06.001","article-title":"Crosstalk between apoptosis, necrosis and autophagy","volume":"1833","author":"Nikoletopoulou","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1177\/1933719113508816","article-title":"Autophagy induced by tumor necrosis factor alpha mediates intrinsic apoptosis in trophoblastic cells","volume":"21","author":"Cha","year":"2014","journal-title":"Reprod. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1002\/stem.2005","article-title":"Icariin promotes angiogenic differentiation and prevents oxidative stress-induced autophagy in endothelial progenitor cells","volume":"33","author":"Tang","year":"2015","journal-title":"Stem Cells"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1159\/000490016","article-title":"By Activating Akt\/eNOS Bilobalide B Inhibits Autophagy and Promotes Angiogenesis Following Focal Cerebral Ischemia Reperfusion","volume":"47","author":"Zheng","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41418-019-0287-8","article-title":"Autophagy in endothelial cells and tumor angiogenesis","volume":"26","author":"Schaaf","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.yjmcc.2007.10.013","article-title":"Stimulation of mitochondrial biogenesis and autophagy by lipopolysaccharide in the neonatal rat cardiomyocyte protects against programmed cell death","volume":"44","author":"Jones","year":"2008","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.tcb.2007.07.009","article-title":"ROS, mitochondria and the regulation of autophagy","volume":"17","author":"Elazar","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1016\/j.juro.2012.12.110","article-title":"Rapamycin attenuates bladder hypertrophy during long-term outlet obstruction in vivo: Tissue, matrix and mechanistic insights","volume":"189","author":"Schroder","year":"2013","journal-title":"J. Urol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhao, J., Song, Q., Wang, L., Dong, X., Yang, X., Bai, X., Song, B., Damaser, M., and Li, L. (2015). Detrusor myocyte autophagy protects the bladder function via inhibiting the inflammation in cyclophosphamide-induced cystitis in rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122597"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.drugalcdep.2015.04.022","article-title":"Serum level of vascular endothelial growth factor decreased in chronic ketamine abusers","volume":"152","author":"Fan","year":"2015","journal-title":"Drug Alcohol. Depend."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/jcp.21924","article-title":"p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress-induced angiogenesis","volume":"222","author":"Gee","year":"2010","journal-title":"J. Cell Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.neuroscience.2013.03.045","article-title":"The regulatory role of NF-kappaB in autophagy-like cell death after focal cerebral ischemia in mice","volume":"244","author":"Li","year":"2013","journal-title":"Neuroscience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.7150\/ijbs.12930","article-title":"Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia","volume":"11","author":"Yang","year":"2015","journal-title":"Int. J. Biol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1186\/s13287-018-1060-5","article-title":"Distinct role of autophagy on angiogenesis: Highlights on the effect of autophagy in endothelial lineage and progenitor cells","volume":"9","author":"Hassanpour","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.mmcr.2014.08.001","article-title":"Multifocal Rhizopus microsporus lung infection following brush clearing","volume":"6","author":"Tsyrkunou","year":"2014","journal-title":"Med. Mycol. Case Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1016\/j.ajpath.2015.04.020","article-title":"Translocation of NF-kappaB and expression of cyclooxygenase-2 are enhanced by ketamine-induced ulcerative cystitis in rat bladder","volume":"185","author":"Juan","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1002\/nau.22367","article-title":"Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder","volume":"32","author":"Chuang","year":"2013","journal-title":"Neurourol. Urodyn."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"F318","DOI":"10.1152\/ajprenal.00607.2014","article-title":"Ketamine-induced ulcerative cystitis and bladder apoptosis involve oxidative stress mediated by mitochondria and the endoplasmic reticulum","volume":"309","author":"Liu","year":"2015","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1111\/jsm.12104","article-title":"Effects of supraphysiological testosterone treatment and orchiectomy on ischemia\/reperfusion-induced bladder dysfunction in male rabbits","volume":"10","author":"Chuang","year":"2013","journal-title":"J. Sex. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s11010-007-9696-y","article-title":"Coenzyme Q10 protect against ischemia\/reperfusion induced biochemical and functional changes in rabbit urinary bladder","volume":"311","author":"Juan","year":"2008","journal-title":"Mol Cell Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.niox.2008.06.221","article-title":"The immediate effect of nitric oxide on the rabbit bladder after ovariectomy","volume":"19","author":"Juan","year":"2008","journal-title":"Nitric. Oxide."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jenvman.2012.06.024","article-title":"Environmental analysis of raw cork extraction in cork oak forests in southern Europe (Catalonia--Spain)","volume":"110","author":"Rives","year":"2012","journal-title":"J. Environ. Manag."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.jdiacomp.2016.08.006","article-title":"Association of neutrophil-lymphocyte ratio with metabolic syndrome and its components in Asian Indians (CURES-143)","volume":"30","author":"Surendar","year":"2016","journal-title":"J. Diabetes Complications"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"418","DOI":"10.4137\/BMI.S294","article-title":"The role of structural extracellular matrix proteins in urothelial bladder cancer (review)","volume":"2","author":"Brunner","year":"2007","journal-title":"Biomark. Insights."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Xu, H., Pumiglia, K., and LaFlamme, S.E. (2020). Laminin-511 and alpha6 integrins regulate the expression of CXCR4 to promote endothelial morphogenesis. J. Cell Sci., 133.","DOI":"10.1242\/jcs.246595"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.3892\/ijo.2014.2631","article-title":"Tie2-dependent deletion of alpha6 integrin subunit in mice reduces tumor growth and angiogenesis","volume":"45","author":"Bouvard","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_40","first-page":"E581","article-title":"The Role of Immunoglobulin E in the Pathogenesis of Ketamine Related Cystitis and Ulcerative Interstitial Cystitis: An Immunohistochemical Study","volume":"19","author":"Jhang","year":"2016","journal-title":"Pain Physician."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1158\/1535-7163.MCT-11-0047","article-title":"The role of autophagy in cancer: Therapeutic implications","volume":"10","author":"Yang","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"13083","DOI":"10.1002\/jcp.27979","article-title":"Rapamycin enhances growth inhibition on urothelial carcinoma cells through LKB1 deficiency-mediated mitochondrial dysregulation","volume":"234","author":"Whang","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_43","first-page":"9208","article-title":"Effect of rapamycin (RAPA) on the growth of lung cancer and its mechanism in mice with A549","volume":"8","author":"Wang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1080\/01616412.2018.1531203","article-title":"Influence of mTOR signaling pathway on ketamine-induced injuries in the hippocampal neurons of rats","volume":"41","author":"Liu","year":"2019","journal-title":"Neurol. Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Gao, L., Jiang, T., Guo, J., Liu, Y., Cui, G., Gu, L., Su, L., and Zhang, Y. (2012). Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046092"}],"updated-by":[{"DOI":"10.3390\/biology14111630","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,5,30]],"date-time":"2021-05-30T00:00:00Z","timestamp":1622332800000}}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/6\/488\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T12:02:43Z","timestamp":1763640163000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/6\/488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,30]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["biology10060488"],"URL":"https:\/\/doi.org\/10.3390\/biology10060488","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,30]]}}}