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）诱导的急性肾损伤（阿基）仍然是老年人的主要临床问题， 人口尽管I/R诱导的阿基发生在各种临床情况中，例如休克、肾损伤、急性 移植、脓毒症和肾动脉狭窄，其机制是多因素的，复杂的， 明白在正常的生理条件下，肾脏在四种气体的帮助下产生硫化氢（H2S）。 酶：胱硫醚β-合酶（CBS）、胱硫醚γ-裂解酶（CSE）、3-巯基丙酮酸硫转移酶 （3 MST）和半胱氨酸氨基转移酶（CAT）。近年来，H2S已被证明调节几种 生理功能，并且其减少与诸如高血压，炎症， 动脉粥样硬化和肾脏疾病进展和衰竭。microRNA（miRNAs）是小的非编码RNA， 其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- 在诱导阿基的过程中，已经报道了几种miRNA的差异表达。此外，在I/R诱导的 阿基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 亚群M2参与炎症反应，亚群M2参与修复机制。我们的初步结果表明， I/R诱导的阿基在衰老的miRNA-21中上调，而miRNA-194下调。受伤的肾脏也 显示CBS和3 MST酶的表达降低，导致H2S产生减少。的 M1/M2比值增高进一步提示炎症期延长。此外，矩阵的表达式 金属蛋白酶-9（MMP-9）及其调节分子EMMPRIN和Meprin-A也上调 在阿基。这些变化与内皮细胞向间质细胞转化（EndoMT）一致，使我们强烈地 相信I/R引起的旧肾的有害重塑。有趣的是，H2S治疗减轻了重塑， 并改善老年小鼠I/R诱导的阿基的肾功能。我们通过miR-21获得了类似的结果 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诱导的衰老肾脏损伤。为了进一步证实我们的概念，男性和女性，老年人和年轻人 野生型（WT，C57 BL/6 J）小鼠将用于比较I/R诱导的肾损伤和功能障碍的严重性， 并将评估H2S处理的有益效果。获得的知识不仅有助于更好地 了解阿基在衰老中的机制，但也将为未来的诊断和治疗提供帮助。 这些策略将适用于患有阿基的老年患者。