Yoshihara Hikari A I, Comment Arnaud, Schwitter Juerg
Laboratory for Functional and Metabolic Imaging, Institute of Physics, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
Front Physiol. 2021 Dec 10;12:792769. doi: 10.3389/fphys.2021.792769. eCollection 2021.
As both a consumer and producer of glucose, the kidney plays a significant role in glucose homeostasis. Measuring renal gluconeogenesis requires invasive techniques, and less invasive methods would allow renal gluconeogenesis to be measured more routinely. Magnetic resonance spectroscopy and imaging of infused substrates bearing hyperpolarized carbon-13 spin labels allows metabolism to be detected within the body with excellent sensitivity. Conversion of hyperpolarized 1-C pyruvate in the fasted rat liver is associated with gluconeogenic flux through phosphoenolpyruvate carboxykinase (PEPCK) rather than pyruvate dehydrogenase (PDH), and this study tested whether this was also the case in the kidney. The left kidney was scanned in fed and overnight-fasted rats either with or without prior treatment by the PEPCK inhibitor 3-mercaptopicolinic acid (3-MPA) following infusion of hyperpolarized 1-C pyruvate. The C-bicarbonate signal normalized to the total metabolite signal was 3.2-fold lower in fasted rats ( = 0.00073) and was not significantly affected by 3-MPA treatment in either nutritional state. By contrast, the normalized [1-C]aspartate signal was on average 2.2-fold higher in the fasted state ( = 0.038), and following 3-MPA treatment it was 2.8-fold lower in fed rats and 15-fold lower in fasted rats ( = 0.001). These results confirm that, unlike in the liver, most of the pyruvate-to-bicarbonate conversion in the fasted kidney results from PDH flux. The higher conversion to aspartate in fasted kidney and the marked drop following PEPCK inhibition demonstrate the potential of this metabolite as a marker of renal gluconeogenesis.
作为葡萄糖的消耗者和生产者，肾脏在葡萄糖稳态中发挥着重要作用。测量肾糖异生需要侵入性技术，而侵入性较小的方法将使肾糖异生的测量更具常规性。磁共振波谱和对带有超极化碳-13自旋标记的注入底物进行成像，能够以极高的灵敏度检测体内的代谢情况。禁食大鼠肝脏中超极化的1-¹³C丙酮酸的转化与通过磷酸烯醇式丙酮酸羧激酶（PEPCK）而非丙酮酸脱氢酶（PDH）的糖异生通量相关，本研究测试了肾脏中是否也是如此。在注入超极化的1-¹³C丙酮酸后，对喂食和禁食过夜的大鼠的左肾进行扫描，扫描前部分大鼠用PEPCK抑制剂3-巯基吡啶甲酸（3-MPA）处理，部分未处理。禁食大鼠中归一化至总代谢物信号的¹³C-碳酸氢盐信号降低了3.2倍（P = 0.00073），且在两种营养状态下3-MPA处理均未对其产生显著影响。相比之下，禁食状态下归一化的[1-¹³C]天冬氨酸信号平均高出2.2倍（P = 0.038），在3-MPA处理后，喂食大鼠中该信号降低了2.8倍，禁食大鼠中降低了15倍（P = 0.001）。这些结果证实，与肝脏不同，禁食肾脏中大部分丙酮酸向碳酸氢盐的转化是由PDH通量导致的。禁食肾脏中向天冬氨酸的转化率较高，且在PEPCK抑制后显著下降，这表明该代谢物作为肾糖异生标志物的潜力。
