miRNA Mechanism of Acute Kidney Injury in Aging

衰老过程中急性肾损伤的 miRNA 机制

• 批准号: 9752532
• 负责人: Utpal Sen
• 金额: $ 55.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-31 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752532
• 关键词: 3-Mercaptopyruvate sulfurtransferase; Acute Renal Failure with Renal Papillary Necrosis; Aging; Angiography; Animals; Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Barium; Bilateral; Blood flow; Cardiac Surgery procedures; Clinical; Collagen; Complex; Creatinine; Cystathionine; Cystathionine beta-Synthase; Cysteine; Deposition; Diagnostic; Disease; Disease Progression; Down-Regulation; Endothelium; Enzymes; Equilibrium; Extracellular Matrix; Failure; Female; Fibrosis; Flow Cytometry; Fluorescein-5-isothiocyanate; Functional disorder; Future; Gelatin Zymography; Gelatinase B; Generations; Glomerular Filtration Rate; Goals; Health; Histology; Hydrogen Sulfide; Hypertension; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Lasers; Lead; Lyase; Matrix Metalloproteinases; Measures; Mediating; Meprin; Mesenchymal; Messenger RNA; Metabolic; Methods; MicroRNAs; Mus; Older Population; Organ Transplantation; Outcome; Peritoneal; Phase; Physiological; Plasma; Play; Population; Prevention strategy; Process; Production; Protective Agents; Proteins; Quality of life; Renal Artery Stenosis; Renal Blood Flow; Renal function; Reperfusion Injury; Reperfusion Therapy; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Roentgen Rays; Sepsis; Severities; Shock; Testing; Therapeutic; Transaminases; Transcript; Translations; Transplantation Surgery; Ultrasonography; Untranslated RNA; Up-Regulation; Vascular Diseases; Western Blotting; base; density; design; differential expression; experimental study; improved; inhibitor/antagonist; injured; kidney dysfunction; kidney fibrosis; kidney vascular structure; macrophage; male; older patient; prevent; renal ischemia; repaired; treatment strategy

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.

项目摘要 缺血/再灌注（I/R）诱导的急性肾脏损伤（AKI）仍然是老年人的主要临床问题 尽管我/r诱导的AKI发生在各种临床情况下，例如休克，肾脏 移植，败血症和肾动脉狭窄，该机制是多因素，复杂且较差的 在正常的生理条件下，肾脏借助四个 酶：胱淀粉β-合酶（CBS），胱淀粉γ-乙醇酶（CSE），3-甲状腺丙酮酸硫酸盐硫酸盐硫酸盐硫酸盐转移酶 （3mst）和半胱氨酸氨基转移酶（CAT）。近年来，H2S已被证明可以调节几个 身体功能及其降低已在高血压，炎症等疾病中浸渍 动脉粥样硬化，肾脏疾病的进展和失败。 microRNA（miRNA）是小的非编码RNA， 它具有通过诱导降解或阻断蛋白质翻译来抑制mRNA转录本的能力。在i/r-中 诱导的AKI，据报道有几种miRNA差异表达。此外，在I/R诱导中 AKI巨噬细胞在炎症和修复过程中起关键作用。而M1子集巨噬细胞是 参与炎症，子集M2参与修复机制。我们的初步结果表明 I/R诱导的AKI在老化miRNA-21中进行了更新，并调节miRNA-194。受伤的肾脏 显示CBS和3MST酶的表达降低，导致H2S产生降低。这 M1/M2的比率增加进一步表明炎症阶段延长。另外，矩阵的表达 金属蛋白酶9（MMP-9）及其调节分子，Emmprin和Meprin-A也已更新 在Aki。这些变化与内皮到间充质转变（endomt）的一致 相信在I/R引起的旧肾脏中进行了有害的重塑。有趣的是，H2S治疗缓解了重塑 并改善了老鼠I/R诱导的AKI的肾功能。我们通过miR-21获得了相似的结果 抑制剂治疗。基于这些初步发现，我们假设H2S是一种保护剂 I/R诱导的肾脏损伤。为了进一步证实我们的概念，无论男女，老年与年轻人 野生型（WT，C57BL/6J）小鼠将用于比较I/R诱导的肾脏损伤和功能障碍的严重程度， 将评估H2S治疗的有益作用。获得的知识不仅有助于改善 了解AKI在衰老中的机制，但也会在未来的诊断和疗法上散发灯光 将适用于患有AKI的老年患者的策略。