Research and Early Development, Bayer Pharmaceuticals, Wuppertal, Germany.
Drug Discovery Sciences, Bayer Pharmaceuticals, Wuppertal, Germany.
Am J Physiol Renal Physiol. 2021 Jan 1;320(1):F61-F73. doi: 10.1152/ajprenal.00373.2020. Epub 2020 Nov 16.
Oxidative stress is a key concept in basic, translational, and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. Although attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically have gained further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells, and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular antioxidative glutathione stores. Vanin-1-deficient mice were shown to be protected against oxidative stress damage. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress-related acute or chronic kidney injury as well. By studying renal ischemia-reperfusion injury in Col4α3 (Alport syndrome) mice and in vitro hypoxia-reoxygenation in human proximal tubular cells we found that treatment with a selective and potent Vanin-1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigation and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.
氧化应激是理解各种疾病（包括心血管和肾脏疾病）病理生理学的基础、转化和临床研究中的一个关键概念。尽管迄今为止，尝试使用氧化还原活性物质直接降低氧化应激的方法在很大程度上未能证明具有临床益处，但通过酶促作用间接对抗氧化应激的方法作为潜在的治疗策略引起了更多关注。潘肽酶 Vanin-1 在肾脏近端肾小管细胞中表达，其反应产物半胱胺被描述为通过抑制细胞抗氧化谷胱甘肽储存的补充来负性影响氧化还原稳态。Vanin-1 缺陷小鼠被证明对氧化应激损伤具有保护作用。本研究的目的是阐明药理学抑制 Vanin-1 是否也能保护小鼠免受与氧化应激相关的急性或慢性肾损伤。通过研究 Col4α3（Alport 综合征）小鼠的肾缺血再灌注损伤和人近端肾小管细胞的体外缺氧再复氧，我们发现，使用选择性和有效的 Vanin-1 抑制剂进行治疗可在体外和体内充分抑制酶活性。然而，代谢和氧化还原稳态的替代参数仅部分且不足够地受到影响。因此，肾小管细胞中的细胞凋亡和活性氧水平以及整体肾功能和纤维化过程并未因 Vanin-1 抑制而得到改善。因此，我们得出结论，Vanin-1 在心血管疾病中的功能需要进一步研究，并且药理学抑制 Vanin-1 对肾脏疾病的治疗的生物学相关性仍有待证明。
