Department of Pediatric Urology, Senior Department of Pediatrics, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China; National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.
Laboratory of Proteomics & Key Laboratory of Protein and Peptide Pharmaceuticals Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
Mol Cell Proteomics. 2023 Mar;22(3):100510. doi: 10.1016/j.mcpro.2023.100510. Epub 2023 Feb 17.
Obstructive nephropathy is one of the leading causes of kidney injury and renal fibrosis in pediatric patients. Although considerable advances have been made in understanding the pathophysiology of obstructive nephropathy, most of them were based on animal experiments and a comprehensive understanding of obstructive nephropathy in pediatric patients at the molecular level remains limited. Here, we performed a comparative proteomics analysis of obstructed kidneys from pediatric patients with ureteropelvic junction obstruction and healthy kidney tissues. Intriguingly, the proteomics revealed extensive metabolic reprogramming in kidneys from individuals with ureteropelvic junction obstruction. Moreover, we uncovered the dysregulation of NAD metabolism and NAD-related metabolic pathways, including mitochondrial dysfunction, the Krebs cycle, and tryptophan metabolism, which led to decreased NAD levels in obstructed kidneys. Importantly, the major NADase CD38 was strongly induced in human and experimental obstructive nephropathy. Genetic deletion or pharmacological inhibition of CD38 as well as NAD supplementation significantly recovered NAD levels in obstructed kidneys and reduced obstruction-induced renal fibrosis, partially through the mechanisms of blunting the recruitment of immune cells and NF-κB signaling. Thus, our work not only provides an enriched resource for future investigations of obstructive nephropathy but also establishes CD38-mediated NAD decline as a potential therapeutic target for obstruction-induced renal fibrosis.
梗阻性肾病是小儿肾损伤和肾纤维化的主要原因之一。尽管在理解梗阻性肾病的病理生理学方面已经取得了相当大的进展，但其中大多数都是基于动物实验，对小儿梗阻性肾病在分子水平上的综合认识仍然有限。在这里，我们对患有肾盂输尿管交界处梗阻的小儿患者和健康肾脏组织的梗阻肾脏进行了比较蛋白质组学分析。有趣的是，蛋白质组学揭示了肾盂输尿管交界处梗阻个体肾脏中广泛的代谢重编程。此外，我们还发现了 NAD 代谢和 NAD 相关代谢途径的失调，包括线粒体功能障碍、克雷布斯循环和色氨酸代谢，导致梗阻肾脏中 NAD 水平降低。重要的是，主要的 NAD 酶 CD38 在人和实验性梗阻性肾病中强烈诱导。CD38 的基因缺失或药物抑制以及 NAD 的补充显著恢复了梗阻肾脏中的 NAD 水平，并减少了梗阻引起的肾纤维化，部分机制是抑制免疫细胞募集和 NF-κB 信号。因此，我们的工作不仅为未来对梗阻性肾病的研究提供了丰富的资源，还确立了 CD38 介导的 NAD 下降作为梗阻性肾纤维化的潜在治疗靶点。
