Mitochondrial injury interferes with endogenous renal repair in experimental renovascular disease

线粒体损伤干扰实验性肾血管疾病的内源性肾修复

• 批准号: 9805789
• 负责人: Alfonso Eirin
• 金额: $ 11.93万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805789
• 关键词: Active Biological Transport; Acute Renal Failure with Renal Papillary Necrosis; Adopted; Adult; Affect; Animal Model; Apoptosis; Attenuated; Award; Cell physiology; Cells; Characteristics; Chronic; Chronic Kidney Failure; Data; Deterioration; Development; Diet; Disease; End stage renal failure; Energy Supply; Epithelial Cells; Family suidae; Fibrosis; Functional disorder; Future; Goals; Grant; Human; Hyperlipidemia; Impairment; Incubated; Individual; Injury; Insulin Resistance; Ischemia; K-Series Research Career Programs; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Magnetic Resonance Imaging; Metabolic; Metabolic syndrome; Mitochondria; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Obesity; Organelles; Oxidation-Reduction; Oxidative Stress; Patients; Peptides; Phenotype; Proliferating; Recovery; Renal Artery Stenosis; Renal function; Reperfusion Injury; Research Personnel; Secondary Hypertension; Structural defect; Structure; System; Techniques; Testing; Thinness; Time; Tubular formation; aging population; career; cell injury; effective intervention; efficacy study; improved; improved functioning; in vivo; innovation; kidney fibrosis; kidney repair; kidney vascular structure; mitochondrial dysfunction; mouse model; novel; novel strategies; paracrine; preservation; prevent; process repeatability; progenitor; programs; public health relevance; renal ischemia; repaired; skills; solute; tool

This application responds to PAR-18-103, “Small Grant Program for NIDDK K01/K08/K23 Recipients (R03)”, which provides NIDDK-supported K01, K08, and K23 recipients support at some point during the final two years of their K award, as they complete their transition to fully independent investigator status. Renovascular disease (RVD) remains an important cause of renal failure in the aging population. My K08 studies showed that RVD in swine induces mitochondrial injury in tubular cells, but whether this reflects the direct effect of ischemia and metabolic abnormalities on tubular cells or defective endogenous repair in the post-stenotic kidney is unknown. RVD presents repeated episodes of insults mimicking acute kidney injury (AKI) from which the kidney can normally recover. CD133+/CD24+ scattered tubular-like cells (STCs) represent a dedifferentiated phenotype that can be adopted by surviving tubular epithelial cells. STCs can proliferate and re-differentiate to replace lost neighboring cells. Our preliminary data suggest that RVD induces structural and functional abnormalities in the swine STC mitochondria, but whether RVD impairs the recovery potential of the kidney is unknown. Detecting STC dysfunction and elucidating the mechanisms responsible may facilitate development of adequate tools to preserve their reparative potency and kidney vitality. The hypothesis underlying this proposal is that RVD induces STC mitochondrial injury that impairs their integrity and function, blunting their overall capacity to repair the kidney. We will employ novel swine models of renal artery stenosis (RAS), metabolic syndrome (MetS), and MetS+RAS that closely mimic the ischemic and metabolic components of human RVD. We will study the efficacy of STCs in a murine model of ischemia reperfusion injury (IRI)-induced AKI. Delivery of swine STCs pretreated with mitochondria-targeted peptides (MTPs) will establish the contribution of mitochondrial dysfunction to STC impairment in RVD. Two specific aims will be pursued: Specific Aim 1 will test the hypothesis that RVD-induced STC mitochondrial injury affects their integrity and function. STCs will be collected from pigs after 16 weeks of Lean or MetS diet with or without RAS. Mitochondrial structure and function, as well as cellular injury and function will be assessed in primary cultures of STCs with and without pre-incubation with MTPs. Specific Aim 2 will test the hypothesis that RVD-induced mitochondrial injury in STCs blunts their capacity to repair in-vivo kidneys after AKI. AKI (IRI) will be induced in mice, and STCs (from Specific Aim 1) or vehicle will be intra-arterially injected 3 days after AKI. Renal function and fibrosis will be studied 2 weeks later. The proposed studies could greatly advance our understanding the vulnerability of this repair system and contribute towards development of strategies for improving the utility and efficacy of kidney repair in renal disease. This proposal is well aligned with the applicant’s career goals and will provide him with unique skills from theoretical and experimental knowledge to technical proficiency for his future independent career.

本申请响应PAR-18-103，“NIDDK K01/K08/K23接受者小额资助计划（R03）”，