PDF(Pubmed)
Abstract：
Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD+-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD+, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries.
摘要：
肾脏疾病,包括慢性肾脏病（CKD），糖尿病肾病，和急性肾损伤（AKI），这是一个巨大的全球卫生负担。肾脏是代谢非常活跃的器官，需要大量的ATP。它们由肾小球和随后的肾小管区室中的高度特化的细胞类型组成，这些细胞可以微调代谢以满足其多种功能。肾细胞代谢缺陷，包括改变的脂肪酸氧化或糖酵解，与AKI和CKD有关。线粒体在肾脏代谢中起着至关重要的作用，和新兴的研究已经确定线粒体沉默调节蛋白（SIRT3，SIRT4和SIRT5）是肾细胞代谢适应的关键调节因子，尤其是SIRT3。Sirtuins属于进化上保守的家族，主要是NAD依赖性脱乙酰酶，脱酰基酶，和ADP-核糖基转移酶。他们对NAD+的依赖，用作共基质，直接将它们的酶活性与细胞的代谢状态联系起来。在肾脏，SIRT3已被描述为在线粒体功能的调节中发挥关键作用，以及抗氧化和抗纤维化反应。已经发现SIRT3在肾脏疾病中不断下调。SIRT3的遗传或药理学上调也与有益的肾脏结果相关。重要的是,实验证据表明，SIRT3可能通过调节参与代谢适应的关键酶的活性，在肾细胞中充当重要的能量传感器。因此，SIRT3的激活可能代表了改善肾细胞能量学的有趣策略。在这次审查中,我们讨论了SIRT3在脂质和葡萄糖代谢以及在生理和病理背景下介导代谢转换中的作用。此外，我们强调了其他线粒体沉默调节蛋白的新兴意义，SIRT4和SIRT5，在肾脏代谢。了解线粒体沉默酶在肾脏疾病中的作用也可能为创新和有效的治疗干预措施开辟新的途径，并最终改善肾损伤的管理。
