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 Sep 30;21(19):7237. doi: 10.3390/ijms21197237.
Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring ( = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes.
母体慢性肾脏病（CKD）可导致胎儿编程不良。一氧化氮（NO）缺乏、肠道微生物失调和妊娠期间肾素-血管紧张素系统（RAS）失调与成年后代高血压的发展有关。我们研究了母体腺嘌呤诱导的 CKD 是否可以在成年雄性后代中引发高血压和肾脏疾病。我们还旨在确定潜在的机制，包括肠道微生物群落组成的改变、三甲胺 N-氧化物（TMAO）增加、NO 生物利用度降低和 RAS 失调。为构建母体 CKD 模型，雌性 Sprague-Dawley 大鼠在怀孕前接受普通饮食（对照组）或添加 0.5%腺嘌呤的饮食（CKD 组）3 周。母鼠在妊娠第 21 天被处死以分析胎盘和胎儿。雄性后代（每组 8 只）在 12 周龄时被处死。腺嘌呤喂养的大鼠出现肾功能障碍、肾小球和肾小管间质损伤、高血压、胎盘异常和胎儿体重减轻。此外，母体腺嘌呤诱导的 CKD 导致成年雄性后代发生高血压和肾脏肥大。这些不良的妊娠和后代结局与肠道微生物群落组成的改变、尿毒症毒素不对称和对称二甲基精氨酸（ADMA 和 SDMA）增加、肠道微生物衍生的尿毒症毒素 TMAO 增加、肠道微生物衍生代谢物乙酸盐和丁酸盐水平降低以及肾内 RAS 失调有关。我们的研究结果表明，腺嘌呤诱导的母体 CKD 可能是研究与尿毒症相关的不良妊娠和后代结局的合适模型。靶向 NO 途径、微生物代谢物 TMAO 和 RAS 可能是改善母体 CKD 诱导的不良妊娠和后代结局的潜在治疗策略。
