miRNA Mechanism of Acute Kidney Injury in Aging

项目摘要 缺血/再灌注(I/R)所致的急性肾损伤(AKI)仍然是老年人的主要临床问题 人口。虽然I/R诱导的AKI在各种临床情况下都会发生，如休克、肾脏 移植、脓毒症和肾动脉狭窄，其机制是多因素的、复杂的和不良的。 明白了。在正常生理条件下，肾脏通过四种途径产生硫化氢。 酶：胱硫醚β合酶、胱硫醚γ裂解酶、3-硫代丙酮酸硫转移酶 (3MST)和半胱氨酸氨基转移酶(CAT)。近年来，硫化氢已被证明可以调节几种 生理功能，它的减少与高血压、炎症、 动脉粥样硬化和肾脏疾病的进展和衰竭。MicroRNA(MiRNAs)是一种小的非编码RNA， 它具有通过诱导降解或阻断蛋白质翻译来抑制mRNA转录的能力。在I/R中- 在诱导的AKI中，有几个miRNAs被报道有差异表达。此外，在I/R诱导的 Aki巨噬细胞在炎症和修复过程中起关键作用。而M1亚群巨噬细胞是 参与炎症反应，M2亚群参与修复机制。我们的初步结果表明， I/R诱导的AKI在衰老的miRNA-21中上调，而miRNA-194下调。受伤的肾脏也 CBS和3MST酶的表达减少，导致硫化氢的产生减少。这个 M1/M2比值升高进一步提示炎症期延长。此外，矩阵的表示 金属蛋白酶-9(MMP9)及其调控分子EMMPRIN和Meprin-A也上调 在AKI。这些变化与内皮向间充质转化(EndoMT)相一致，导致我们强烈地 相信I/R诱导的旧肾发生了有害的重塑。有趣的是，硫化氢处理减轻了重塑。 改善老年小鼠缺血再灌注急性肾损伤的肾功能。我们通过miR-21得到了类似的结果 抑制剂治疗。根据这些初步发现，我们假设硫化氢是一种保护剂 I/R致衰老肾脏损伤的实验研究为了进一步证实我们的概念，无论是男性还是女性，老与年轻 野生型(WT，C57BL/6J)小鼠将被用来比较I/R引起的肾脏损伤和功能障碍的严重程度， 并对硫化氢处理的有益效果进行评估。所获得的知识不仅有助于更好地 了解AKI在衰老中的机制，但也将为未来的诊断和治疗提供帮助 适用于老年AKI患者的策略。

Project Summary Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) remains a major clinical problem in older population. Although I/R-induced AKI occurs in a variety of clinical situations such as shock, renal transplantation, sepsis and renal artery stenosis, the mechanism is multifactorial, complex and poorly understood. Under normal physiological conditions, kidney produces hydrogen sulfide (H2S) with the aid of four enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3MST), and cysteine aminotransferase (CAT). In recent years, H2S has been shown to regulate several physiological functions, and its decrease has been implicated in diseases such as hypertension, inflammation, atherosclerosis, and renal disease progression and failure. MicroRNA’s (miRNAs) are small non-coding RNA’s, which has the ability to inhibit mRNA transcripts by inducing degradation or blocking protein translation. In I/R- induced AKI, several miRNAs have been reported to be differentially expressed. Furthermore, in I/R-induced AKI macrophages play a key role in inflammatory and reparative process. While M1 subset macrophage is involved in inflammation, subset M2 is involved in repair mechanism. Our preliminary results suggested that in I/R-induced AKI in aging miRNA-21 is upregulated and miRNA-194 is down regulated. The injured kidney also showed decreased expression of CBS and 3MST enzymes leading to diminished H2S production. The increased ratio of M1/M2 further suggested prolonged inflammatory phase. In addition, expression of matrix metalloproteinase-9 (MMP-9) and their regulatory molecules, EMMPRIN and Meprin-A were also upregulated in AKI. These changes in concert with endothelial to mesenchymal transition (EndoMT) led us to strongly believing a detrimental remodeling in I/R-induced old kidney. Interestingly, H2S treatment mitigated remodeling and improved renal function in I/R-induced AKI in old mice. We obtained similar results through miR-21 inhibitor treatments. Based on these preliminary findings, we hypothesize that H2S is a protective agent against I/R-induced damage in aging kidney. In further substantiating our concept, both male and female, old vs young wild type (WT, C57BL/6J) mice will be used to compare severity of I/R-induced kidney injury and dysfunction, and beneficial effects of H2S treatment will be assessed. The gained knowledge will not only help to better understand mechanisms of AKI in aging, but will also shed lights on future diagnostic and therapeutic strategies which will be applicable to older patients suffering from AKI.