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:
  • 金额:
    $ 14.2万
  • 依托单位:
  • 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

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.
项目摘要 糖尿病肾病(DKD)是慢性和终末期肾病的主要原因, 其特征在于尿白蛋白排泄过多,随后肾功能丧失。在DKD中,超过- 过滤的白蛋白和/或白蛋白结合的棕榈酸(PA)的重吸收, 人尿液中的脂肪酸(FA)可导致肾小管细胞损伤和活化,这可能与 间质纤维化的诱导和肾功能的慢性降低。然而,分子链 在DKD进展过程中肾小管和间质细胞之间的关系尚不清楚。肾损伤分子-1(KIM-1) 1)是肾近端小管(PT)损伤的非侵入性生物标志物, 上皮细胞吞噬脂蛋白和凋亡细胞的清道夫受体。我们假设 KIM-1与STAT 3相互作用以放大PA-白蛋白重吸收能力并促进脂毒性- 在进行性DKD中诱导肾小管间质纤维化。我们将从以下几个方面探讨这一假设: 具体目的:目的I将在体内确定KIM-1在肾小管脂质积聚、STAT 3 活化和肾小管间质纤维化。系统研究将 进行1)进行KIM-1表达、脂质积累、STAT 3 激活,以及相关的脂毒性和纤维化在早期,中期和晚期阶段的DKD在野生型, 型和eNOS-/-小鼠和2)确定KIM-1缺乏对肾小管脂质积累的影响, 高脂饮食喂养的糖尿病KIM-1中STAT 3激活、肾小管间质炎症和纤维化 缺陷型(Kim-1-/-)和Kim-1-/-/eNOS-/-小鼠。目的II将在体外确定KIM的作用和调节- 1和STAT 3在原代培养细胞和成熟近端小管中对不同FA-白蛋白的响应 超载。我们将描述不同FA结合的白蛋白对KIM-1,p-STAT 3, 和脂毒性,通过评估细胞ATP消耗、细胞内脂质沉积、自噬活性和 二维细胞培养物和稳定的人类小管中的ER应激、细胞死亡和溶酶体氧化应激。 此外,我们将检查KIM-1或STAT 3抑制或过表达是否会影响PA-白蛋白 在2D细胞培养物和3D类器官中,过载诱导的脂毒性和STAT 3活化。后 完成这些实验后,我们希望KIM-1将成为一个药物靶点, DKD的预防和治疗。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Xueying Zhao其他文献

Xueying Zhao的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Xueying Zhao', 18)}}的其他基金

KIM-1, microparticles and diabetic tubular injury
KIM-1、微粒和糖尿病肾小管损伤
  • 批准号:
    8214447
  • 财政年份:
    2012
  • 资助金额:
    $ 14.2万
  • 项目类别:
KIM-1, microparticles and diabetic tubular injury
KIM-1、微粒和糖尿病肾小管损伤
  • 批准号:
    8432030
  • 财政年份:
    2012
  • 资助金额:
    $ 14.2万
  • 项目类别:
KIM-1, microparticles and diabetic tubular injury
KIM-1、微粒和糖尿病肾小管损伤
  • 批准号:
    8619621
  • 财政年份:
    2012
  • 资助金额:
    $ 14.2万
  • 项目类别:
KIDNEY INJURY MOLECULE-1 AND DIABETIC NEPHROPATHY
分子 1 肾损伤和糖尿病肾病
  • 批准号:
    8359905
  • 财政年份:
    2011
  • 资助金额:
    $ 14.2万
  • 项目类别:
RENAL CYTOCHROME P450 EPOXYGENASE IN DIABETIC METABOLIC SYNDROME
糖尿病代谢综合征中的肾细胞色素 P450 环氧合酶
  • 批准号:
    8357157
  • 财政年份:
    2011
  • 资助金额:
    $ 14.2万
  • 项目类别:
RENAL CYTOCHROME P450 EPOXYGENASE IN DIABETIC METABOLIC SYNDROME
糖尿病代谢综合征中的肾细胞色素 P450 环氧合酶
  • 批准号:
    8166169
  • 财政年份:
    2010
  • 资助金额:
    $ 14.2万
  • 项目类别:
RENAL CYTOCHROME P450 EPOXYGENASE IN DIABETIC METABOLIC SYNDROME
糖尿病代谢综合征中的肾细胞色素 P450 环氧合酶
  • 批准号:
    7959161
  • 财政年份:
    2009
  • 资助金额:
    $ 14.2万
  • 项目类别:
RENAL CYTOCHROME P450 EPOXYGENASE IN DIABETIC METABOLIC SYNDROME
糖尿病代谢综合征中的肾细胞色素 P450 环氧合酶
  • 批准号:
    7715267
  • 财政年份:
    2008
  • 资助金额:
    $ 14.2万
  • 项目类别:

相似海外基金

Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8390748
  • 财政年份:
    2012
  • 资助金额:
    $ 14.2万
  • 项目类别:
Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8514570
  • 财政年份:
    2012
  • 资助金额:
    $ 14.2万
  • 项目类别:
Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8668774
  • 财政年份:
    2012
  • 资助金额:
    $ 14.2万
  • 项目类别:
Ultrasound-Assisted AQP1 Gene Therapy for Functional Restoration of Salivary Glan
超声辅助 AQP1 基因治疗唾液腺功能恢复
  • 批准号:
    8878038
  • 财政年份:
    2012
  • 资助金额:
    $ 14.2万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了