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Cisplatin is an effective chemotherapeutic agent widely used for the treatment of various solid tumors. However, cisplatin has an important limitation in its use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Thrombomodulin (TM) is well known not only for its role as a cofactor in the clinically important natural anticoagulation pathway but also for its anti-inflammatory properties. Here, we investigated the effects of TM in cisplatin-induced AKI. In mice intraperitoneally injected with 15 mg/kg cisplatin, TM (10 mg/kg) or PBS was administered intravenously at 24 h after cisplatin injection. TM significantly attenuated cisplatin-induced nephrotoxicity with the suppressed elevation of blood urea nitrogen and serum creatinine, and reduced histological damages. Actually, TM treatment significantly alleviated oxidative stress-induced apoptosis by reducing reactive oxygen species (ROS) levels in cisplatin-treated renal proximal tubular epithelial cells (RPTECs) in vitro. Furthermore, TM clarified cisplatin-induced apoptosis by reducing caspase-3 levels. In addition, TM attenuated the endoplasmic reticulum (ER) stress signaling pathway in both renal tissues and RPTECs to protect the kidneys from cisplatin-induced AKI. These findings suggest that TM is a potential protectant against cisplatin-induced nephrotoxicity through suppressing ROS generation and ER stress in response to cisplatin.

Titel:	Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress.
Autor/in / Beteiligte Person:	Yamamoto, H ; Ishida, Y ; Zhang, S ; Osako, M ; Nosaka, M ; Kuninaka, Y ; Ishigami, A ; Iwahashi, Y ; Aragane, M ; Matsumoto, L ; Kimura, A ; Kondo, T
Link:	Full Text Finder (Volltext)
Zeitschrift:	Scientific reports, Jg. 14 (2024-06-18), Heft 1, S. 14004
Veröffentlichung:	London : Nature Publishing Group, copyright 2011-, 2024
Medientyp:	academicJournal
ISSN:	2045-2322 (electronic)
DOI:	10.1038/s41598-024-64619-y
Schlagwort:	Animals Mice Male Kidney drug effects Kidney metabolism Kidney pathology Antineoplastic Agents adverse effects Antineoplastic Agents toxicity Mice, Inbred C57BL Blood Urea Nitrogen Signal Transduction drug effects Kidney Tubules, Proximal drug effects Kidney Tubules, Proximal metabolism Kidney Tubules, Proximal pathology Cisplatin adverse effects Thrombomodulin metabolism Endoplasmic Reticulum Stress drug effects Oxidative Stress drug effects Acute Kidney Injury chemically induced Acute Kidney Injury metabolism Acute Kidney Injury drug therapy Acute Kidney Injury pathology Reactive Oxygen Species metabolism Apoptosis drug effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Sci Rep] 2024 Jun 18; Vol. 14 (1), pp. 14004. <i>Date of Electronic Publication: </i>2024 Jun 18. MeSH Terms: Cisplatin* / adverse effects ; Thrombomodulin* / metabolism ; Endoplasmic Reticulum Stress* / drug effects ; Oxidative Stress* / drug effects ; Acute Kidney Injury* / chemically induced ; Acute Kidney Injury* / metabolism ; Acute Kidney Injury* / drug therapy ; Acute Kidney Injury* / pathology ; Reactive Oxygen Species* / metabolism ; Apoptosis* / drug effects ; Animals ; Mice ; Male ; Kidney / drug effects ; Kidney / metabolism ; Kidney / pathology ; Antineoplastic Agents / adverse effects ; Antineoplastic Agents / toxicity ; Mice, Inbred C57BL ; Blood Urea Nitrogen ; Signal Transduction / drug effects ; Kidney Tubules, Proximal / drug effects ; Kidney Tubules, Proximal / metabolism ; Kidney Tubules, Proximal / pathology References: Nat Rev Nephrol. 2018 Oct;14(10):607-625. (PMID: 30135570) ; Exp Toxicol Pathol. 2009 May;61(3):223-42. (PMID: 18986801) ; J Am Soc Nephrol. 2009 Mar;20(3):524-34. (PMID: 19176699) ; Oxid Med Cell Longev. 2020 Feb 6;2020:7912763. 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(PMID: 3102062) Grant Information: 22K10617 Grants-in-Aids for Scientific Research (C); 22K10615 Grants-in-Aids for Scientific Research (C); 23K09770 Grants-in-Aids for Scientific Research (C); 22K10618 Grants-in-Aids for Scientific Research (C); 22K19676 Challenging Exploratory Research; 22H03366 Grants-in-Aids for Scientific Research (B) Contributed Indexing: Keywords: Acute kidney injury; Cisplatin; Mice; Thrombomodulin; Tubular cells Substance Nomenclature: Q20Q21Q62J (Cisplatin) ; 0 (Thrombomodulin) ; 0 (Reactive Oxygen Species) ; 0 (Antineoplastic Agents) Entry Date(s): Date Created: 20240618 Date Completed: 20240618 Latest Revision: 20240624 Update Code: 20240625 PubMed Central ID: PMC11189513

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Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress.