Weber Gregory J, Foster Jaleyea, Pushpakumar Sathnur B, Sen Utpal
Department of Physiology, University of Louisville, School of Medicine, Louisville, KY, 40202, United States.
Department of Physiology, University of Louisville, School of Medicine, Louisville, KY, 40202, United States.
Pharmacol Res. 2018 Aug;134:157-165. doi: 10.1016/j.phrs.2018.06.012. Epub 2018 Jun 15.
Hypertension affects nearly one third of the adult US population and is a significant risk factor for chronic kidney disease (CKD). An expanding body of recent studies indicates that gut microbiome has crucial roles in regulating physiological processes through, among other mechanisms, one mode of short chain fatty acids (SCFA) and their target receptors. In addition, these SCFA receptors are potential targets of regulation by host miRNAs, however, the mechanisms through which this occurs is not clearly defined. Hydrogen sulfide (HS) is an important gasotransmitter involved in multiple physiological processes and is known to alleviate adverse effects of hypertension such as reducing inflammation in the kidney. To determine the role of host microRNAs in regulating short chain fatty acid receptors in the kidney as well as the gut, C57BL/6J wild-type mice were treated with or without Ang-II and HS donor GYY4137 (GYY) for 4 weeks to assess whether GYY would normalize adverse effects observed in hypertensive mice and whether this was in part due to altered gut microbiome composition. We observed several changes of SCFA receptors, including Olfr78, Gpr41/43 and predicted microRNA regulators in the kidney among the different treatments. Increased expression of inflammatory markers Il6 and Rorc2, along with Tgfβ, were found in the hypertensive kidney. The glomerular filtration rate (GFR) was improved in mice treated with Ang-II + GYY compared with Ang-II only, indicating improved kidney function. The Erysipelotrichia class of bacteria, linked with high fat diets, was enriched in hypertensive animals but reduced with GYY supplementation. These data point towards a role for miRNA regulation of SCFA receptors in hypertensive kidney and are normalized by HS supplementation.
高血压影响了近三分之一的美国成年人口，是慢性肾脏病（CKD）的一个重要风险因素。最近越来越多的研究表明，肠道微生物群通过短链脂肪酸（SCFA）及其靶受体等机制在调节生理过程中发挥关键作用。此外，这些SCFA受体是宿主微小RNA（miRNA）潜在的调控靶点，然而，其发生机制尚不清楚。硫化氢（HS）是一种参与多种生理过程的重要气体信号分子，已知可减轻高血压的不良反应，如减轻肾脏炎症。为了确定宿主miRNA在调节肾脏和肠道中短链脂肪酸受体的作用，将C57BL/6J野生型小鼠分为接受或未接受血管紧张素II（Ang-II）和HS供体GYY4137（GYY）处理4周的两组，以评估GYY是否能使高血压小鼠中观察到的不良反应恢复正常，以及这是否部分归因于肠道微生物群组成的改变。我们观察到在不同处理组中，肾脏中SCFA受体（包括Olfr78、Gpr41/43）以及预测的miRNA调节因子发生了一些变化。在高血压肾脏中发现炎症标志物Il6、Rorc2以及转化生长因子β（Tgfβ）的表达增加。与仅接受Ang-II处理的小鼠相比，接受Ang-II + GYY处理的小鼠的肾小球滤过率（GFR）有所改善，表明肾功能得到改善。与高脂饮食相关的丹毒丝菌纲细菌在高血压动物中富集，但在补充GYY后减少。这些数据表明miRNA在高血压肾脏中对SCFA受体具有调节作用，并且补充HS可使其恢复正常。
