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Functional Significance of Ferritin Light Chain in Sepsis-associated Kidney Injury

铁蛋白轻链在脓毒症相关肾损伤中的功能意义

基本信息

批准号：
10117517
负责人：
Subhashini Bolisetty
金额：
$ 36.15万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117517
关键词：
Acute Renal Failure with Renal Papillary Necrosis Biogenesis Cathepsins Cells Clinical Research Creatinine Critical Illness Cystatins Data Development Disease Endotoxemia Extracellular Signal Regulated Kinases Ferritin Functional disorder Gene Expression Genes Genetic Glycolysis Health Expenditures Homeostasis Hypoxia Inducible Factor In Vitro Infection Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Injury to Kidney Intensive Care Units Interleukin-6 Iron Kidney Knowledge LCN2 gene Left Light Lipopolysaccharides Mediating Mediator of activation protein Metabolism Mitochondria Modeling Morbidity - disease rate Mus Myelogenous Myeloid Cells Oxidative Stress PPAR gamma Pathogenesis Pathogenicity Patients Phenotype Physiological Population Production Proteins Proximal Kidney Tubules Recombinants Renal function Reporting Role Saline Sepsis Serum Signal Transduction Site TNF gene Testing Therapeutic Transgenic Mice Tubular formation Up-Regulation Wild Type Mouse Work carboxypeptidase C cecal ligation puncture clinically relevant cytokine cytokine release syndrome design gain of function immunoregulation in vivo Model inhibitor/antagonist kidney cell loss of function macrophage mitochondrial dysfunction mortality mortality risk mouse model neutrophil novel overexpression peroxisome preclinical study preservation prevent rat KIM-1 protein response single-cell RNA sequencing success therapeutic target therapeutically effective tool transcriptome transcriptome sequencing

项目摘要

Sepsis accounts for nearly 50% of acute kidney injury (AKI) in the intensive care unit and significantly impacts mortality. However, therapy for sepsis-associated AKI (SA-AKI) has remained elusive because the pathophysiology of injury is not well understood. Evidence emphasizes the pathogenic role of systemic cytokine storm and proximal tubular damage (oxidative stress and mitochondrial dysfunction) in SA-AKI. The cytokine response, mediated by NFkB and HIF-1α signaling in myeloid cells (particularly, macrophages) is a dominant pathogenic mechanism in sepsis. In this context, treatment of macrophages with ferritin light chain (FtL) reduces lipopolysaccharide (LPS)-induced activation of NFkB and HIF-1α and subsequent pro-inflammatory gene expression (IL-6, TNFα). Additionally, administration of FtL to wildtype mice mitigates cecal ligation and puncture (CLP) induced hyperinflammation. Single cell RNA sequencing on renal cell populations from mice administered FtL (or saline) and then subjected to LPS endotoxemia identified cystatin A (CSTA) as the most significantly upregulated gene in the myeloid populations of FtL administered mice. CSTA is an intracellular inhibitor of cathepsins. While the role of CSTA in sepsis is unknown, cathepsins augment the inflammatory response via activation of NFκB. Therefore, we propose that FtL prevents the hyperinflammatory response via CSTA- mediated inhibition of cathepsin and NFκB/HIF-1α signaling during sepsis. Pertinent to the kidney, while CLP led to marked expression of kidney injury markers (NGAL and KIM-1), FtL administration prevented such induction and preserved expression of peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC-1α), a regulator of mitochondrial biogenesis and metabolism. Proximal tubules (PT) are the sites of maximal injury during sepsis and FtL is expressed in this tubular segment. Thus, we propose to determine the disparate roles of macrophage- and PT-derived FtL in the protective response during sepsis. Our findings are clinically relevant because serum ferritin levels (predominantly FtL) are often elevated during inflammation but its role in inflammation is unknown. We propose that an increase in FtL is an adaptive physiological response to control inflammation and promote survival. In Aim 1, using two models of sepsis (CLP and LPS) combined with novel tools to delete or overexpress FtL, we will determine whether FtL induces CSTA expression and inhibits macrophage HIF-1α signaling, thereby preventing mitochondrial dysfunction, glycolysis and subsequently mitigating overproduction of cytokines. In Aim 2, we will determine the distinct functional roles of macrophage vs. PT-specific FtL expression in mitigating loss of kidney function, renal inflammation, oxidative stress and mitochondrial dysfunction. Using an integrative approach of in vitro and in vivo models, we will determine the function of FtL during sepsis. If our hypothesis is validated, the results will justify the development of a new treatment for SA-AKI that could alleviate the significant burden of sepsis induced morbidity, mortality and substantial health care expenditures.

脓毒症占重症监护病房急性肾损伤（AKI）的近50%，影响显著