Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Vegetative Physiologie, Berlin, Germany.
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik m.S. Nephrologie und Internistische Intensivmedizin, Berlin, Germany.
Kidney Int. 2022 Oct;102(4):750-765. doi: 10.1016/j.kint.2022.04.025. Epub 2022 May 26.
Chronic Cyclosporine-A treatment is associated with serious side effects, including kidney toxicity and anemia. Although pathophysiology of Cyclosporine-A-induced kidney injury remains incompletely understood, hypoxia is likely involved. Here, we investigated the effect of the hypoxia inducible factor activator daprodustat on Cyclosporine-A -induced kidney toxicity. As Cyclosporine-A profoundly alters protein phosphorylation by inhibiting the phosphatase calcineurin, special attention was directed towards the kidney phospho-proteome. Mice received Cyclosporine-A with or without daprodustat for up to eight weeks. In kidney homogenates, 1360 selected proteins were analyzed at expression and phosphorylation levels. Of these, Cyclosporine-A changed the expression of 79 and the phosphorylation of 86 proteins. However, when Cyclosporine-A treatment was combined with daprodustat, the expression of 95 proteins and phosphorylation of only six proteins was altered suggesting that daprodustat prevented most protein phosphorylation brought about by Cyclosporine-A. Although daprodustat showed only marginal effect on its own, angiogenesis-related pathways were among the most profoundly impacted by daprodustat when given on top of Cyclosporine-A. Additionally, Cyclosporine-A lowered the blood hemoglobin concentration and caused kidney capillary rarefaction, which daprodustat prevented. Thus, combined daprodustat/Cyclosporine-A treatment prevented deleterious Cyclosporine-A effects on microcirculation and hemoglobin, and the protective action of daprodustat involves suppression of broad protein phosphorylation changes caused by Cyclosporine-A.
慢性环孢素 A 治疗与严重的副作用有关，包括肾毒性和贫血。虽然环孢素 A 诱导的肾损伤的病理生理学仍不完全清楚，但缺氧可能参与其中。在这里，我们研究了缺氧诱导因子激活剂 daprodustat 对环孢素 A 诱导的肾毒性的影响。由于环孢素 A 通过抑制磷酸酶钙调神经磷酸酶显著改变蛋白质磷酸化，因此特别关注肾脏磷酸化蛋白质组。小鼠接受环孢素 A 加或不加 daprodustat 长达八周。在肾匀浆中，分析了 1360 种选定蛋白质的表达和磷酸化水平。其中，环孢素 A 改变了 79 种蛋白质的表达和 86 种蛋白质的磷酸化。然而，当环孢素 A 治疗与 daprodustat 联合使用时，只有 95 种蛋白质的表达和 6 种蛋白质的磷酸化发生改变，这表明 daprodustat 阻止了环孢素 A 引起的大多数蛋白质磷酸化。尽管 daprodustat 本身的作用很小，但当与环孢素 A 一起使用时，血管生成相关途径是受 daprodustat 影响最深远的途径之一。此外，环孢素 A 降低了血液血红蛋白浓度并导致肾脏毛细血管稀疏，而 daprodustat 可预防这种情况。因此，联合使用 daprodustat/环孢素 A 可预防环孢素 A 对微循环和血红蛋白的有害影响，而 daprodustat 的保护作用涉及抑制环孢素 A 引起的广泛蛋白质磷酸化变化。
