Immunosuppression with cyclosporine versus tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

IF 5.6 2区医学 Q1 PHYSIOLOGY Acta Physiologica Pub Date : 2024-06-17 DOI:10.1111/apha.14190

Hasan Demirci, Suncica Popovic, Carsten Dittmayer, Duygu Elif Yilmaz, Ismail Amr El-Shimy, Michael Mülleder, Christian Hinze, Mingzhen Su, Philipp Mertins, Marieluise Kirchner, Bilgin Osmanodja, Alexander Paliege, Klemens Budde, Kerstin Amann, Pontus B. Persson, Kerim Mutig, Sebastian Bachmann

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Abstract

Aim

Calcineurin inhibitors (CNIs) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects contribute to allograft injury. Renal parenchymal lesions occur for cyclosporine A (CsA) as well as for the currently favored tacrolimus (Tac). We aimed to study whether chronic CsA and Tac exposures, before reaching irreversible nephrotoxic damage, affect renal compartments differentially and whether related pathogenic mechanisms can be identified.

Methods

CsA and Tac were administered chronically in wild type Wistar rats using osmotic minipumps over 4 weeks. Functional parameters were controlled. Electron microscopy, confocal, and 3D-structured illumination microscopy were used for histopathology. Clinical translatability was tested in human renal biopsies. Standard biochemical, RNA-seq, and proteomic technologies were applied to identify implicated molecular pathways.

Results

Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction, enhanced apoptosis, impaired proteostasis and oxidative stress. Lesion characteristics were confirmed in human renal biopsies.

Conclusion

We conclude that pathogenetic alterations in the renal compartments are specific for either treatment. Considering translation to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share protein signatures identified from multiomics with potential pathognomonic relevance.

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环孢素与他克莫司的免疫抑制作用在肾脏内显示出不同的肾毒性特征。

目的：钙神经蛋白抑制剂（CNIs）是实体器官移植后免疫抑制的主要药物。虽然它们能成功预防肾移植排斥反应，但其肾毒性副作用也会造成异体移植损伤。环孢素 A（CsA）和目前常用的他克莫司（Tac）都会引起肾实质病变。我们的目的是研究慢性 CsA 和 Tac 暴露在达到不可逆的肾毒性损伤之前是否会对肾脏分区产生不同的影响，以及是否能确定相关的致病机制：方法：使用渗透式微型泵对野生型 Wistar 大鼠进行为期 4 周的 CsA 和 Tac 慢性给药。控制功能参数。组织病理学采用电子显微镜、共聚焦和三维结构照明显微镜。在人体肾活检中测试了临床可转化性。应用标准生化、RNA-seq和蛋白质组学技术鉴定相关分子通路：结果：两种药物都对血管和肾小球造成了明显的损伤，但损伤程度不同。Tac对肾小球滤过屏障的影响比CsA更大，内皮细胞和荚膜细胞明显退化，血管内皮生长因子/血管内皮生长因子受体2信号传导和荚膜细胞特异性基因表达受损。相比之下，近端肾小管上皮细胞受 CsA 的影响比受 Tac 的影响更严重，表现出溶酶体功能障碍、细胞凋亡增强、蛋白稳态受损和氧化应激。病变特征在人体肾活检中得到了证实：我们得出的结论是，肾脏结构的病理改变对两种治疗方法都有特异性。考虑到临床应用，选择氯化萘类药物应反映肾血管和肾小管上皮的个体风险因素。作为朝这一方向迈出的一步，我们分享了从多组学中发现的具有潜在病理相关性的蛋白质特征。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Physiologica 医学-生理学

CiteScore

11.80

自引率

15.90%

发文量

182

审稿时长

4-8 weeks

期刊介绍： Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.