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: 9947747
• 负责人: Utpal Sen
• 金额: $ 54.53万
• 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/9947747
• 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 to Kidney; 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; 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; kidney dysfunction; kidney fibrosis; kidney vascular structure; macrophage; male; older patient; prevent; renal ischemia; repaired; reparative process; 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.

项目概要 缺血/再灌注（I/R）引起的急性肾损伤（AKI）仍然是老年人的主要临床问题 尽管 I/R 诱发的 AKI 发生在多种临床情况下，例如休克、肾损伤等。 移植、脓毒症和肾动脉狭窄，其机制是多因素、复杂且较差的 据了解，在正常生理条件下，肾脏在四种物质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 (3MST) 和半胱氨酸转氨酶 (CAT) 近年来，H2S 已被证明可以调节多种酶。 生理功能，其减少与高血压、炎症、 动脉粥样硬化、肾脏疾病进展和衰竭。MicroRNA (miRNA) 是小非编码 RNA， 它能够通过诱导降解或阻断 I/R- 蛋白翻译来抑制 mRNA 转录。 据报道，在 I/R 诱导的 AKI 中，一些 miRNA 存在差异表达。 AKI 巨噬细胞在炎症和修复过程中发挥着关键作用，而 M1 亚群巨噬细胞则发挥着关键作用。 我们的初步结果表明，M2 亚群参与炎症，参与修复机制。 缺血再灌注诱导的 AKI 中衰老的 miRNA-21 上调，受损肾脏中的 miRNA-194 也下调。 显示 CBS 和 3MST 酶表达减少，导致 H2S 产量减少。 M1/M2 比率的增加进一步表明炎症期延长。此外，基质的表达也增加。 金属蛋白酶-9 (MMP-9) 及其调节分子 EMMPRIN 和 Meprin-A 也上调 在 AKI 中，这些变化与内皮细胞间质转化 (EndoMT) 相结合，使我们强烈地 相信缺血再灌注引起的旧肾的重塑，H2S 治疗可减轻重塑。 我们通过 miR-21 获得了类似的结果。 基于这些初步发现，我们发现 H2S 是一种针对 H2S 的保护剂。 缺血再灌注引起的衰老肾脏损伤进一步证实了我们的概念，无论是男性还是女性、老年人还是年轻人。 野生型（WT、C57BL/6J）小鼠将用于比较 I/R 诱导的肾损伤和功能障碍的严重程度， 并评估 H2S 处理的有益效果。所获得的知识不仅有助于更好地进行。 AKI 的衰老机制，同时也将为未来的诊断和治疗提供线索 适用于患有 AKI 的老年患者的策略。