引言
急性肾损伤(acute kidney injury, AKI)是一个具有挑战性的临床问题,与高发病率和死亡率有关,是新冠肺炎危重患者的常见并发症。在急性肾损伤中,肾小管上皮细胞(tubular epithelial cells,TEC)是损伤的主要部位,急性肾损伤的恢复取决于TEC的可塑性【1】。在急性损伤的肾脏中,适宜的应激反应促使修复机制被适当激活,使损伤后的肾脏得以完全修复【1】。然而,如果肾脏应激反应过度,AKI导致的损伤则不能完全修复并进展为慢性肾损伤(chronic kidney injury, CKD),甚至导致慢性肾脏疾病及肾衰竭【2】。由于AKI导致的应激反应预示着CKD的进展,因此预防或停止不良应激反应不仅在急性损伤阶段具有核心临床重要性,在损伤后修复阶段仍具有重大意义【3】。然而,肾小管上皮细胞对应激反应的细胞机制尚不完全清楚,在急性肾损伤过程中是否应该使用糖皮质激素仍没有达成共识。
近日,由西南医科大学附属医院内分泌科徐勇科研团队成员周路平博士后为第一作者、德国马尔堡大学药理学研究所的Thomas Worzfeld教授为通讯作者的文章Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury在Science Translational Medicine杂志在线发表。该研究通过RNA seq、ATAC seq、肾脏TEC糖皮质激素受体(glucocorticoid receptor, GR)特异性敲除、DNA损伤及代谢分析,揭示TEC的不良应激反应在急性损伤及修复中的分子机制和药理靶点,为进一步理解合成糖皮质激素(如地塞米松)加剧肾脏的急性损伤提供新的视角。

参考文献
1. M. Chang-Panesso, B. D. Humphreys, Cellular plasticity in kidney injury and repair. Nat.Rev. Nephrol. 13, 39–46 (2017).2. S. A. Strausser, D. Nakano, T. Souma, Acute kidney injury to chronic kidney disease transition: Insufficient cellular stress response. Curr. Opin. Nephrol. Hypertens. 27, 314–322(2018).3. L . S. Chawla, P. W. Eggers, R. A. Star, P. L. Kimmel, Acute kidney injury and chronic kidney disease as interconnected syndromes. N. Engl. J. Med. 371, 58–66 (2014).4. F. Schutgens, M. B. Rookmaaker, T. Margaritis, A. Rios, C. Ammerlaan, J. Jansen, L. Gijzen, M. Vormann, A. Vonk, M. Viveen, F. Y. Yengej, S. Derakhshan, K. M. de Winter-de Groot, B. Artegiani, R. van Boxtel, E. Cuppen, A. P. A. Hendrickx, M. M. van den Heuvel-Eibrink, E. Heitzer, H. Lanz, J. Beekman, J.-L. Murk, R. Masereeuw, F. Holstege, J. Drost, M. C. Verhaar, H. Clevers, Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat. Biotechnol. 37, 303–313 (2019).5. K. Chapman, M. Holmes, J. Seckl, 11β-hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action. Physiol. Rev. 93, 1139–1206 (2013).6. I . Shimizu, Y. Yoshida, M. Suda, T. Minamino, DNA damage response and metabolic disease. Cell Metab. 20, 967–977 (2014).7. A . J. Rose, A. Vegiopoulos, S. Herzig, Role of glucocorticoids and the glucocorticoid receptor in metabolism: Insights from genetic manipulations. J. Steroid Biochem. Mol. Biol. 122, 10–20 (2010).8. R . A. Saxton, D. M. Sabatini, mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).https://pubmed.ncbi.nlm.nih.gov/39356748/责编|探索君
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文章来源|“BioArt”
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