Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida; Tampa, FL 33602, U.S.A.
Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC 29425, U.S.A.
Clin Sci (Lond). 2024 Mar 6;138(5):269-288. doi: 10.1042/CS20231144.
The development of the kidney involves essential cellular processes, such as cell proliferation and differentiation, which are led by interactions between multiple signaling pathways. Xanthine dehydrogenase (XDH) catalyzes the reaction producing uric acid in the purine catabolism, which plays a multifaceted role in cellular metabolism. Our previous study revealed that the genetic ablation of the Xdh gene in rats leads to smaller kidneys, kidney damage, decline of renal functions, and failure to thrive. Rats, unlike humans, continue their kidney development postnatally. Therefore, we explored whether XDH plays a critical role in kidney development using SS-/- rats during postnatal development phase. XDH expression was significantly increased from postnatal day 5 to 15 in wild-type but not homozygote rat kidneys. The transcriptomic profile of renal tissue revealed several dysregulated pathways due to the lack of Xdh expression with the remodeling in inflammasome, purinergic signaling, and redox homeostasis. Further analysis suggested that lack of Xdh affects kidney development, likely via dysregulation of epidermal growth factor and its downstream STAT3 signaling. The present study showed that Xdh is essential for kidney maturation. Our data, alongside the previous research, suggests that loss of Xdh function leads to developmental issues, rendering them vulnerable to kidney diseases in adulthood.
肾脏的发育涉及重要的细胞过程，如细胞增殖和分化，这些过程由多个信号通路之间的相互作用所主导。黄嘌呤脱氢酶（XDH）催化嘌呤分解代谢中产生尿酸的反应，在细胞代谢中发挥着多方面的作用。我们之前的研究表明，大鼠 Xdh 基因的遗传缺失会导致肾脏变小、肾脏损伤、肾功能下降和生长不良。与人类不同的是，大鼠在出生后仍在继续肾脏发育。因此，我们使用 SS-/- 大鼠在出生后发育阶段探索了 XDH 是否在肾脏发育中发挥关键作用。野生型大鼠肾脏中 XDH 的表达从出生后第 5 天到第 15 天显著增加，但在纯合子大鼠肾脏中则没有增加。由于缺乏 Xdh 表达，肾脏组织的转录组谱显示了几个失调的途径，包括炎症小体、嘌呤能信号和氧化还原稳态的重塑。进一步的分析表明，缺乏 Xdh 会影响肾脏发育，可能是通过表皮生长因子及其下游 STAT3 信号的失调。本研究表明 Xdh 对肾脏成熟是必需的。我们的数据以及之前的研究表明，Xdh 功能的丧失会导致发育问题，使它们在成年后易患肾脏疾病。
