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Molecular mechanisms underlying renal lipotoxicity and DKD progression

肾脂毒性和 DKD 进展的分子机制

基本信息

批准号：
10629589
负责人：
Xueying Zhao
金额：
$ 14.2万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629589
关键词：
3-Dimensional AQP1 gene Acute Affect Albumins Albuminuria Alloxan Animals Apical Apoptosis Apoptotic Autophagocytosis Binding Biochemical Pathway Biological Markers C57BL/6 Mouse Cell Culture System Cell Culture Techniques Cell Death Cells Chronic Chronic Kidney Failure DNA Damage Data Deposition Diabetic Nephropathy Differentiation Antigens Disease Progression Disease model End stage renal failure Endocytosis Epithelial Cells Epithelium Excretory function Fatty Acids Fibroblasts Fibrosis Genetic Transcription Geometry Goals High Fat Diet Human In Vitro Inflammation Inflammatory Injury to Kidney Kidney Kidney Diseases Knockout Mice LDL-Receptor Related Protein 2 Ligands Link Lipids Lipoproteins Mediating Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Translocation Obesity Onset of illness Organoids Oxidative Stress Palmitic Acids Pathologic Pathway interactions Pericytes Phagocytosis Pilot Projects Prevention Primary Cell Cultures Profibrotic signal Proteins Proteinuria Proximal Kidney Tubules Regulation Renal function Research Role STAT3 gene Saturated Fatty Acids Severities Signal Transduction Surface Tubular formation Up-Regulation Urine absorption cell injury cytotoxicity diabetic druggable target endoplasmic reticulum stress experimental study in vivo interstitial interstitial cell kidney cell monolayer novel novel therapeutic intervention overexpression prevent promoter rat KIM-1 protein response scavenger receptor spatiotemporal trafficking transcriptome sequencing two-dimensional uptake urinary

项目摘要

Project Summary Diabetic kidney disease (DKD), the leading cause of chronic and end stage renal disease, is characterized by excessive urinary albumin excretion followed by loss of kidney function. In DKD, over- reabsorption of filtered albumin and/or albumin-bound palmitic acid (PA), the most abundant saturated fatty acid (FA) in human urine, could lead to tubular cell injury and activation, which may be involved in the induction of interstitial fibrosis and chronic reduction of renal function. However, the molecular link between tubular and interstitial cells during DKD progression is not clear. Kidney injury molecule-1 (KIM- 1) is a noninvasive biomarker for renal proximal tubule (PT) damage and has been identified as a scavenger receptor for epithelial phagocytosis of lipoproteins and apoptotic cells. We hypothesize that KIM-1 interacts with STAT3 to amplify PA-albumin reabsorption capacity and promote lipotoxicity- induced tubulointerstitial fibrosis in progressive DKD. The hypothesis will be pursued with the following specific aims: Aim I will in vivo determine the role of KIM-1 in tubular lipid accumulation, STAT3 activation, and tubulointerstitial fibrosis during DKD onset and progression. Systematic studies will be conducted to 1) conduct spatiotemporal analysis of KIM-1 expression, lipid accumulation, STAT3 activation, and associated lipotoxicity and fibrosis in early, middle and advanced stages of DKD in wild- type and eNOS-/- mice and 2) determine the effects of KIM-1 deficiency on tubular lipid accumulation, STAT3 activation, and tubulointerstitial inflammation and fibrosis in high-fat diet-fed diabetic KIM-1- deficient (Kim-1-/-) and Kim-1-/-/eNOS-/- mice. Aim II will in vitro determine the role and regulation of KIM- 1 and STAT3 in primary cultured cells and mature proximal tubuloids in response to different FA-albumin overload. We will delineate the differential effects of different FA-bound albumin on KIM-1, p-STAT3, and lipotoxicity by evaluating cell ATP depletion, intracellular lipid deposition, autophagy activity and ER stress, cell death, and lysosomal oxidative stress in both 2D cell culture and stable human tubuloids. In addition, we will examine if KIM-1 or STAT3 inhibition or overexpression would affect PA-albumin overload-induced lipotoxicity and STAT3 activation in both 2D cell cultures and 3D organoids. Upon completion of these experiments we are hopeful that KIM-1 will emerge as a druggable target for the prevention and treatment of DKD.

项目总结