{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:57:38Z","timestamp":1785430658201,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Korean society of Nephrology","award":["2023-31-0699"],"award-info":[{"award-number":["2023-31-0699"]}]},{"award":["2023-31-0699"],"award-info":[{"award-number":["2023-31-0699"]}],"id":[{"id":"https:\/\/ror.org\/01rncwg06","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Faculty Research Grant of Yonsei University College of Medicine","award":["6-2023-0091"],"award-info":[{"award-number":["6-2023-0091"]}]},{"award":["6-2023-0091"],"award-info":[{"award-number":["6-2023-0091"]}],"id":[{"id":"https:\/\/ror.org\/01wjejq96","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases involved in collagen cross-linking, has emerged as a key mediator of pathological extracellular matrix remodeling and tissue fibrosis. Dysregulated LOXL2 activity has been implicated in various fibrotic diseases; however, its role in fibrosis-driven chronic kidney injury, particularly in the context of calcineurin inhibitor-induced kidney toxicity, remains incompletely defined. Methods To investigate the contribution of LOXL2 inhibitor to cyclosporine A (CsA)-induced nephropathy, a well-established model of progressive tubulointerstitial fibrosis, male CD-1 mice were administered either saline or CsA (15 mg\/kg\/day, intraperitoneally) for 8 weeks. After 4 weeks of CsA exposure, CsA-treated mice were further divided into two groups and received either vehicle or a LOXL2 inhibitor (10 mg\/kg\/day, oral gavage) for an additional 4 weeks. Kidney function, albuminuria, histological fibrosis, inflammatory cell infiltration, and profibrotic gene expression were assessed. Results In a murine model of CsA-induced nephropathy, pharmacological inhibition of LOXL2 markedly improved kidney outcomes. LOXL2 inhibition significantly reduced albuminuria and ameliorated kidney dysfunction. In parallel, tubulointerstitial fibrosis was substantially attenuated, accompanied by reduced myofibroblast activation and extracellular matrix accumulation. These protective effects were associated with downregulation of profibrotic and inflammatory mediators and inhibition of TGF-\u03b2-related downstream signaling pathways activated by CsA. Conclusions The present preclinical findings suggest that Compound #765-mediated LOXL2 inhibition may offer a potential therapeutic benefit in CsA-induced fibrosis, though further validation is warranted.<\/jats:p>","DOI":"10.3390\/ph19060960","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"960","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expression of Lysyl Oxidase-Related Protein and Effect of Lysyl Oxidase Inhibition in Cyclosporine-Induced Nephropathy Mouse Model"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7654-8473","authenticated-orcid":false,"given":"Hyo Jeong","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, National Health Insurance Service Medical Center, Ilsan Hospital, 100 Ilsan-ro, Goyang 10444, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Hyun","family":"Jhee","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4245-0339","authenticated-orcid":false,"given":"Hoon Young","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea"},{"name":"Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5273-3113","authenticated-orcid":false,"given":"Jae Myun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1550-0812","authenticated-orcid":false,"given":"Hyeong Cheon","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Republic of Korea"},{"name":"Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153544","DOI":"10.1016\/j.tox.2023.153544","article-title":"Role of cyclosporin A in the treatment of kidney disease and nephrotoxicity","volume":"492","author":"Yu","year":"2023","journal-title":"Toxicology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1681\/ASN.2010060673","article-title":"Epithelial-to-mesenchymal transition predicts cyclosporine nephrotoxicity in renal transplant recipients","volume":"22","author":"Hazzan","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"481","DOI":"10.2215\/CJN.04800908","article-title":"Calcineurin inhibitor nephrotoxicity","volume":"4","author":"Naesens","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1016\/j.bbrc.2018.07.014","article-title":"Differential expression of cyclosporine A-Induced calcineurin isoform-specific matrix metalloproteinase 9 (MMP-9) in renal fibroblasts","volume":"503","author":"Francis","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1042\/EBC20180050","article-title":"Lysyl oxidases: From enzyme activity to extracellular matrix cross-links","volume":"63","author":"Vallet","year":"2019","journal-title":"Essays Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zaffryar-Eilot, S., and Hasson, P. (2022). Lysyl Oxidases: Orchestrators of Cellular Behavior and ECM Remodeling and Homeostasis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911378"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s12967-024-06056-z","article-title":"LOX-induced tubulointerstitial fibrosis via the TGF-\u03b2\/LOX\/Snail axis in diabetic mice","volume":"23","author":"Lu","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.1038\/s41467-025-61795-x","article-title":"Inhibition of epithelial cell YAP-TEAD\/LOX signaling attenuates pulmonary fibrosis in preclinical models","volume":"16","author":"Wagner","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1136\/gutjnl-2016-312473","article-title":"Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal","volume":"66","author":"Ikenaga","year":"2017","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1038\/s41467-020-16199-4","article-title":"Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer","volume":"11","author":"Saatci","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.taap.2011.02.015","article-title":"Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model","volume":"252","author":"Slattery","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1081\/JDI-120005360","article-title":"Oxidative stress-mediated renal dysfunction by cyclosporine A in rats: Attenuation by trimetazidine","volume":"24","author":"Satyanarayana","year":"2002","journal-title":"Ren. Fail."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1093\/joneph\/18.4.453","article-title":"Oxidative and nitrosative stress in kidney disease: A case for cyclosporine A","volume":"18","author":"Lamas","year":"2005","journal-title":"J. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.fct.2018.06.054","article-title":"Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings","volume":"118","author":"Wu","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"220s","DOI":"10.1016\/j.transproceed.2004.01.028","article-title":"Cyclosporine nephrotoxicity","volume":"36","year":"2004","journal-title":"Transpl. Proc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s12307-012-0105-z","article-title":"Lysyl oxidase, extracellular matrix remodeling and cancer metastasis","volume":"5","author":"Xiao","year":"2012","journal-title":"Cancer Microenviron."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nrc3319","article-title":"The rationale for targeting the LOX family in cancer","volume":"12","author":"Barker","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Klepfish, M., Gross, T., Vugman, M., Afratis, N.A., Havusha-Laufer, S., Brazowski, E., Solomonov, I., Varol, C., and Sagi, I. (2020). LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00480"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1183\/09031936.00141013","article-title":"Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression","volume":"43","author":"Chien","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/s41598-017-00270-0","article-title":"Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis","volume":"7","author":"Aumiller","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13710","DOI":"10.1038\/ncomms13710","article-title":"Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment","volume":"7","author":"Yang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.1186\/1755-1536-5-S1-S16","article-title":"Hypoxia-inducible factor signaling in the development of kidney fibrosis","volume":"5","author":"Haase","year":"2012","journal-title":"Fibrogenesis Tissue Repair."},{"key":"ref_23","first-page":"3810","article-title":"Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition","volume":"117","author":"Higgins","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.kint.2018.02.024","article-title":"Lysyl oxidase like-2 contributes to renal fibrosis in Col4\u03b13\/Alport mice","volume":"94","author":"Cosgrove","year":"2018","journal-title":"Kidney Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9423","DOI":"10.1038\/s41598-018-27462-6","article-title":"Lysyl oxidase-like 2 inhibition ameliorates glomerulosclerosis and albuminuria in diabetic nephropathy","volume":"8","author":"Stangenberg","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1002\/jcp.30717","article-title":"Disulfiram prevents collagen crosslinking and inhibits renal fibrosis by inhibiting lysyl oxidase enzymes","volume":"237","author":"Saifi","year":"2022","journal-title":"J. Cell Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Shim, D.H., Kim, M.J., Chung, H.W., Kim, M.N., Sohn, M.H., Lee, S., Kim, I., Lee, C.G., Elias, J.A., and Park, J.H. (2026). Targeting Lysyl Oxidase-like 2: A Therapeutic Strategy for Idiopathic Pulmonary Fibrosis with a Novel Indolizine Derivative. 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