Weber Gregory J, Pushpakumar Sathnur B, Sen Utpal
Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.
Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
Am J Physiol Heart Circ Physiol. 2017 May 1;312(5):H874-H885. doi: 10.1152/ajpheart.00637.2016. Epub 2017 Feb 17.
Hypertension is a major risk factor for chronic kidney disease (CKD), and renal inflammation is an integral part in this pathology. Hydrogen sulfide (HS) has been shown to mitigate renal damage through reduction in blood pressure and ROS; however, the exact mechanisms are not clear. While several studies have underlined the role of epigenetics in renal inflammation and dysfunction, the mechanisms through which epigenetic regulators play a role in hypertension are not well defined. In this study, we sought to identify whether microRNAs are dysregulated in response to angiotensin II (ANG II)-induced hypertension in the kidney and whether a HS donor, GYY4137, could reverse the microRNA alteration and kidney function. Wild-type (C57BL/6J) mice were treated without or with ANG II and GYY4137 for 4 wk. Blood pressure, renal blood flow, and resistive index (RI) were measured. MicroRNA microarrays were conducted and subsequent target prediction revealed genes associated with a proinflammatory response. ANG II treatment significantly increased blood pressure, decreased blood flow in the renal cortex, increased RI, and reduced renal function. These effects were ameliorated in mice treated with GYY4137. Microarray analysis revealed downregulation of miR-129 in ANG II-treated mice and upregulation after GYY4137 treatment. Quantitation of proteins involved in the inflammatory response and DNA methylation revealed upregulation of IL-17A and DNA methyltransferase 3a, whereas HS production enzymes and anti-inflammatory IL-10 were reduced. Taken together, our data suggest that downregulation of miR-129 plays a significant role in ANG II-induced renal inflammation and functional outcomes and that GYY4137 improves renal function by reversing miR-129 expression. We investigated epigenetic changes that occur in the hypertensive kidney and how HS supplementation reverses adverse effects. Inflammation, aberrant methylation, and dysfunction were observed in the hypertensive kidney, and these effects were alleviated with HS supplementation. We identify miR-129 as a potential regulator of blood pressure and HS regulation.
高血压是慢性肾脏病（CKD）的主要危险因素，肾脏炎症是这一病理过程的一个组成部分。硫化氢（HS）已被证明可通过降低血压和活性氧（ROS）来减轻肾脏损伤；然而，确切机制尚不清楚。虽然多项研究强调了表观遗传学在肾脏炎症和功能障碍中的作用，但表观遗传调节因子在高血压中发挥作用的机制尚未明确。在本研究中，我们试图确定微小RNA（miRNA）是否在肾脏中因血管紧张素II（ANG II）诱导的高血压而失调，以及HS供体GYY4137是否能逆转miRNA改变和肾功能。野生型（C57BL/6J）小鼠接受4周无或有ANG II和GYY4137的治疗。测量血压、肾血流量和阻力指数（RI）。进行miRNA微阵列分析，随后的靶标预测揭示了与促炎反应相关的基因。ANG II治疗显著升高血压，降低肾皮质血流量，增加RI，并降低肾功能。在用GYY4137治疗的小鼠中，这些作用得到改善。微阵列分析显示，ANG II治疗的小鼠中miR-129下调，而GYY4137治疗后上调。对参与炎症反应和DNA甲基化的蛋白质进行定量分析显示，白细胞介素-17A（IL-17A）和DNA甲基转移酶3a上调，而HS产生酶和抗炎性IL-10减少。综上所述，我们的数据表明，miR-129下调在ANG II诱导的肾脏炎症和功能结局中起重要作用，并且GYY4137通过逆转miR-129表达来改善肾功能。我们研究了高血压肾脏中发生的表观遗传变化以及补充HS如何逆转不良影响。在高血压肾脏中观察到炎症、异常甲基化和功能障碍，补充HS可减轻这些影响。我们确定miR-129是血压和HS调节的潜在调节因子。
