Franzin Rossana, Stasi Alessandra, Ranieri Elena, Netti Giuseppe Stefano, Cantaluppi Vincenzo, Gesualdo Loreto, Stallone Giovanni, Castellano Giuseppe
Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy.
Clinical Pathology, Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
Front Pharmacol. 2021 Apr 29;12:630419. doi: 10.3389/fphar.2021.630419. eCollection 2021.
The biological process of renal aging is characterized by progressive structural and functional deterioration of the kidney leading to end-stage renal disease, requiring renal replacement therapy. Since the discovery of pivotal mechanisms of senescence such as cell cycle arrest, apoptosis inhibition, and the development of a senescence-associated secretory phenotype (SASP), efforts in the understanding of how senescent cells participate in renal physiological and pathological aging have grown exponentially. This has been encouraged by both preclinical studies in animal models with senescent cell clearance or genetic depletion as well as due to evidence coming from the clinical oncologic experience. This review considers the molecular mechanism and pathways that trigger premature renal aging from mitochondrial dysfunction, epigenetic modifications to autophagy, DNA damage repair (DDR), and the involvement of extracellular vesicles. We also discuss the different pharmaceutical approaches to selectively target senescent cells (namely, senolytics) or the development of systemic SASP (called senomorphics) in basic models of CKD and clinical trials. Finally, an overview will be provided on the potential opportunities for their use in renal transplantation during machine perfusion to improve the quality of the graft.
肾脏衰老的生物学过程表现为肾脏结构和功能的渐进性恶化，最终导致终末期肾病，需要进行肾脏替代治疗。自从发现衰老的关键机制，如细胞周期停滞、凋亡抑制以及衰老相关分泌表型（SASP）的形成以来，人们对衰老细胞如何参与肾脏生理和病理衰老的理解呈指数级增长。动物模型中衰老细胞清除或基因缺失的临床前研究以及临床肿瘤学经验提供的证据都推动了这一进展。本综述探讨了从线粒体功能障碍、表观遗传修饰到自噬、DNA损伤修复（DDR）以及细胞外囊泡的参与等引发肾脏早衰的分子机制和途径。我们还讨论了在慢性肾脏病基础模型和临床试验中，针对衰老细胞进行选择性靶向治疗（即衰老细胞溶解剂）或开发全身性SASP（称为衰老细胞形态调节剂）的不同药物方法。最后，将概述它们在肾脏移植机器灌注过程中用于提高移植物质量的潜在机会。
