Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Buck Institute for Research on Aging, Novato, California, United States.
Am J Physiol Renal Physiol. 2024 Jul 1;327(1):F128-F136. doi: 10.1152/ajprenal.00062.2024. Epub 2024 May 2.
Acute kidney injury (AKI) is extremely prevalent among hospitalizations and presents a significant risk for the development of chronic kidney disease and increased mortality. Ischemia caused by shock, trauma, and transplant are common causes of AKI. To attenuate ischemic AKI therapeutically, we need a better understanding of the physiological and cellular mechanisms underlying damage. Instances of ischemia are most damaging in proximal tubule epithelial cells (PTECs) where hypoxic signaling cascades, and perhaps more rapidly, posttranslational modifications (PTMs), act in concert to change cellular metabolism. Here, we focus on the effects of the understudied PTM, lysine succinylation. We have previously shown a protective effect of protein hypersuccinylation on PTECs after depletion of the desuccinylase sirtuin5. General trends in the results suggested that hypersuccinylation led to upregulation of peroxisomal activity and was protective against kidney injury. Included in the list of changes was the Parkinson's-related deglycase Park7. There is little known about any links between peroxisome activity and Park7. In this study, we show in vitro and in vivo that Park7 has a crucial role in protection from AKI and upregulated peroxisome activity. These data in combination with published results of Park7's protective role in cardiovascular damage and chronic kidney disease lead us to hypothesize that succinylation of Park7 may ameliorate oxidative damage resulting from AKI and prevent disease progression. This novel mechanism provides a potential therapeutic mechanism that can be targeted. Succinylation is an understudied posttranslational modification that has been shown to increase peroxisomal activity. Furthermore, increased peroxisomal activity has been shown to reduce oxidative stress and protect proximal tubules after acute kidney injury. Analysis of mass spectrometry succinylomic and proteomic data reveals a novel role for Parkinson's related Park7 in mediating Nrf2 antioxidant response after kidney injury. This novel protection pathway provides new insights for kidney injury prevention and development of novel therapeutics.
急性肾损伤（AKI）在住院患者中极为普遍，是慢性肾脏病和死亡率增加的重要危险因素。休克、创伤和移植引起的缺血是 AKI 的常见原因。为了在治疗上减轻缺血性 AKI，我们需要更好地了解损伤的生理和细胞机制。在近端肾小管上皮细胞（PTECs）中，缺氧信号级联反应，也许更快的是，翻译后修饰（PTMs），协同作用改变细胞代谢，缺血情况最具破坏性。在这里，我们专注于研究研究较少的翻译后修饰赖氨酸琥珀酰化的作用。我们之前已经表明，在去琥珀酰酶 Sirtuin5 耗尽后，PTECs 中的蛋白质过度琥珀酰化具有保护作用。结果的总体趋势表明，过度琥珀酰化导致过氧化物酶体活性上调，并对肾损伤具有保护作用。变化列表中包括与帕金森病相关的去糖基化酶 Park7。过氧化物酶体活性与 Park7 之间的任何联系知之甚少。在这项研究中，我们在体外和体内证明 Park7 在保护 AKI 和上调过氧化物酶体活性方面起着至关重要的作用。这些数据与 Park7 在心血管损伤和慢性肾脏病中的保护作用的已发表结果相结合，使我们假设 Park7 的琥珀酰化可能减轻 AKI 引起的氧化损伤并防止疾病进展。这种新的机制提供了一个潜在的治疗机制，可以作为靶点。琥珀酰化是一种研究较少的翻译后修饰，已被证明可以增加过氧化物酶体活性。此外，过氧化物酶体活性增加已被证明可以减少急性肾损伤后氧化应激并保护近端肾小管。对质谱琥珀酰基组学和蛋白质组学数据的分析揭示了帕金森病相关 Park7 在介导肾损伤后 Nrf2 抗氧化反应中的新作用。这种新的保护途径为肾损伤预防和新型治疗药物的开发提供了新的见解。
