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.

项目总结