Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Int J Mol Sci. 2020 Jun 26;21(12):4552. doi: 10.3390/ijms21124552.
Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin-angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague-Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups ( = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD.
高血压和慢性肾脏病（CKD）可发生于生命早期。不同途径生成的色氨酸代谢产物既有有害作用，也有有益作用。在 CKD 中，色氨酸生成代谢产物的尿毒症毒素是芳烃受体（AHR）的内源性配体。AHR、一氧化氮（NO）、肾素-血管紧张素系统（RAS）和肠道微生物群之间的相互作用参与了高血压的发生。我们研究了母体 CKD 能否通过上述机制在妊娠期间补充色氨酸来预防成年后代的高血压和肾脏疾病。给予 Sprague-Dawley（SD）雌性大鼠普通饮食或补充 0.5%腺嘌呤的饮食 3 周，以在妊娠前诱导 CKD。妊娠对照组或 CKD 大鼠在妊娠期间经口灌胃给予载体或色氨酸 200 mg/kg/天。雄性后代分为四组（每组 8 只）：对照组、CKD 组、色氨酸补充组（Trp）和 CKD 加色氨酸补充组（CKDTrp）。所有大鼠在 12 周龄时处死。我们发现母体 CKD 导致成年后代高血压，而色氨酸补充可预防。母体 CKD 诱导的高血压与 NO 生物利用度降低和非经典 RAS 轴有关。母体 CKD 和色氨酸补充以不同的方式在成年后代中塑造了不同的肠道微生物群谱。色氨酸补充对母体 CKD 诱导的程序性高血压的保护作用与几种色氨酸代谢微生物和 AHR 信号通路的改变有关。我们的研究结果支持色氨酸代谢微生物群、AHR、NO 和 RAS 在发育起源性高血压中的相互作用。此外，妊娠期间补充色氨酸可能是预防母体 CKD 引起的高血压的一种潜在方法。
