丙酮酸脱氢酶与钙调磷酸酶抑制剂诱导的肾纤维化的细胞代谢。

IF 9.4 1区医学 Q1 UROLOGY & NEPHROLOGY

Journal of The American Society of Nephrology Pub Date : 2025-08-29 DOI:10.1681/ASN.0000000855

Yasuhiro Oda, Hiroshi Nishi, Fumie Hamano, Teruhiko Yoshida, Yoshihiro Kita, Jeffrey B Kopp, Masaomi Nangaku

引用次数: 0

摘要

背景：钙调磷酸酶抑制剂是移植受者和自身免疫性疾病患者不可缺少的免疫抑制剂，但长期使用会导致肾毒性，包括肾纤维化。为什么抑制钙调磷酸酶（一种丝氨酸/苏氨酸磷酸酶）会导致肾纤维化尚未完全阐明。方法：为了在单细胞分辨率下表征慢性钙调磷酸酶抑制剂肾毒性早期的表型变化，对慢性钙调磷酸酶抑制剂肾毒性小鼠模型及其对照组的肾脏组织进行了单核RNA测序。ICR小鼠饲喂低钠饮食，并给予环孢素a 30 mg/kg/d、他克莫司3 mg/kg/d或对照药，持续4周。用环孢素A、他克莫司或载药培养原代人肾近端小管上皮细胞。结果：慢性钙调磷酸酶抑制剂肾毒性小鼠模型的肾脏单核RNA测序发现，损伤的近端小管细胞比例更高，这些细胞表现出与氧化磷酸化、细胞衰老和纤维化相关基因的表达改变。对公开获得的人类肾脏转录组的分析证实，在某些条件下，在人类同种异体移植肾脏中观察到一些这些表现。在培养的原代人肾近端小管上皮细胞中，钙调磷酸酶抑制剂引起丙酮酸脱氢酶的磷酸化（失活），线粒体代谢受损和衰老相关表型，所有这些都通过丙酮酸脱氢酶的激活得到改善。最后，在慢性钙调磷酸酶抑制剂肾毒性小鼠模型中，给药二氯乙酸（一种已知的丙酮酸脱氢酶激活剂）减轻了肾纤维化，增加了编码电子传递链组分的基因表达，降低了与近端小管损伤、细胞衰老和纤维化相关的基因表达。结论：钙调磷酸酶抑制使丙酮酸脱氢酶失活，引起近端小管细胞代谢功能障碍，引起纤维化表型。近端小管细胞代谢功能障碍可能是慢性钙调磷酸酶抑制剂肾毒性的一个特征，出现在早期阶段。

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来源期刊

Journal of The American Society of Nephrology 医学-泌尿学与肾脏学

CiteScore

22.40

自引率

2.90%

发文量

492

审稿时长

3-8 weeks

期刊介绍： The Journal of the American Society of Nephrology (JASN) stands as the preeminent kidney journal globally, offering an exceptional synthesis of cutting-edge basic research, clinical epidemiology, meta-analysis, and relevant editorial content. Representing a comprehensive resource, JASN encompasses clinical research, editorials distilling key findings, perspectives, and timely reviews. Editorials are skillfully crafted to elucidate the essential insights of the parent article, while JASN actively encourages the submission of Letters to the Editor discussing recently published articles. The reviews featured in JASN are consistently erudite and comprehensive, providing thorough coverage of respective fields. Since its inception in July 1990, JASN has been a monthly publication. JASN publishes original research reports and editorial content across a spectrum of basic and clinical science relevant to the broad discipline of nephrology. Topics covered include renal cell biology, developmental biology of the kidney, genetics of kidney disease, cell and transport physiology, hemodynamics and vascular regulation, mechanisms of blood pressure regulation, renal immunology, kidney pathology, pathophysiology of kidney diseases, nephrolithiasis, clinical nephrology (including dialysis and transplantation), and hypertension. Furthermore, articles addressing healthcare policy and care delivery issues relevant to nephrology are warmly welcomed.