Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease

KLF6 在糖尿病肾病中对线粒体功能的转录控制

基本信息

项目摘要

Project Summary/Abstract The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans have chronic kidney disease. Diabetes Mellitus is the leading risk factor for chronic kidney disease in the United States. Despite improved glycemic control, individuals with Diabetes Mellitus continue to develop and progress to diabetic kidney disease (DKD). In DKD, along with endothelial injury and mesangial expansion, podocyte loss directly contributes to the functional capacity to maintain the renal filtration barrier. Mitochondrial injury is also uniformly observed in DKD and is accompanied by mitochondrial DNA damage as well as altered expression of genes involved in mitochondrial biogenesis, function, and fragmentation. We recently reported the essential role for the zinc-finger transcription factor, Krüppel-like factor 6 (KLF6), in podocyte injury. Specifically, we demonstrated that KLF6 is an early inducible injury response gene that enhances mitochondrial respiratory complex IV (cytochrome c oxidase, COX) expression, thereby abrogating the release of cytochrome c and activation of apoptosis in the setting of cell stress. KLF6 maintains COX assembly by regulating the expression of key transcripts involved in mitochondrial replication, transcription, and function under cell stress. To date, this is the first study demonstrating a direct regulatory effect of a zinc-finger transcription factor on mitochondrial function in the podocyte. Our preliminary data also suggests that podocyte-specific loss of Klf6 (Klf6-/-) accelerated DKD in mice. In addition, we observed a significant increase in mitochondrial injury with podocyte loss in the diabetic Klf6-/- mice as compared to diabetic wildtype mice. Furthermore, we observed that modulating the level of KLF6 expression in the podocyte directly regulated mitochondrial structure, function, genes involved in COX assembly, and apoptosis. Finally, KLF6 expression was reduced in DKD as compared to healthy control subjects in three independent gene expression arrays from human kidney biopsies. The objective of this research proposal is to demonstrate that KLF6 is required to prevent mitochondrial dysfunction and podocyte injury in DKD. The long-term goal of our project is to identify “druggable” targets in restoring mitochondrial function in podocytes of diabetic kidney. This proposal will address a current gap in the field by demonstrating that COX assembly is critical to preventing mitochondrial dysfunction in podocytes of diabetic kidney. The potential impact of this proposed research is that it will shed new light on the critical role of respiratory complex assembly in improving mitochondrial function in the podocyte and slowing the rate of DKD progression in the kidney. Finally, deciphering the mechanism by which KLF6 regulates COX assembly will provide us with a novel pathway to target in DKD.
项目总结/摘要 疾病控制和预防中心估计,美国超过10%的成年人, 2000万美国人患有慢性肾病。糖尿病是慢性糖尿病的主要危险因素。 肾病在美国尽管血糖控制得到改善,但糖尿病患者 继续发展并进展为糖尿病肾病(DKD)。在DKD中,沿着内皮损伤, 肾小球系膜扩张,足细胞损失直接有助于维持肾滤过的功能能力 屏障线粒体损伤在DKD中也是一致的,并伴有线粒体DNA损伤。 损伤以及参与线粒体生物发生、功能和 碎片化我们最近报道了锌指转录因子Krüppel样因子的重要作用, 6(KLF 6),在足细胞损伤中。具体地说,我们证明KLF 6是一种早期可诱导的损伤反应, 增强线粒体呼吸复合物IV(细胞色素c氧化酶,考克斯)表达的基因,从而 在细胞应激的情况下消除细胞色素C的释放和细胞凋亡的激活。KLF 6保持 考克斯组装通过调节参与线粒体复制的关键转录物的表达, 转录和在细胞应激下的功能。到目前为止,这是第一个研究表明,直接调控 锌指转录因子对足细胞线粒体功能的影响。我们的初步数据还 提示足细胞特异性Klf 6丢失(Klf 6-/-)加速小鼠中的DKD。此外,我们还观察到, 糖尿病Klf 6-/-小鼠中线粒体损伤与足细胞损失的显著增加, 糖尿病野生型小鼠。此外,我们观察到,调节足细胞中KLF 6的表达水平, 直接调节线粒体结构、功能、参与考克斯组装和凋亡的基因。最后, 与健康对照组相比,DKD患者KLF 6的表达在三个独立的基因中降低, 来自人类肾脏活组织检查的表达阵列。这项研究的目的是证明 KLF 6是防止DKD中线粒体功能障碍和足细胞损伤所必需的。的长期目标 我们的项目是确定恢复糖尿病肾脏足细胞线粒体功能的“药物”靶点。 该提案将通过证明考克斯组装对于 预防糖尿病肾脏足细胞线粒体功能障碍。这一提议的潜在影响 研究表明,它将揭示呼吸复合体组装在改善呼吸系统功能方面的关键作用。 在足细胞中的线粒体功能和减缓肾脏中DKD进展的速率。最后, 破译KLF 6调节考克斯组装的机制将为我们提供一种新的途径, 目标在DKD。

项目成果

期刊论文数量(0)
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Sandeep K Mallipattu其他文献

The Prevalence of Post-Acute Sequelae of COVID-19 in Solid Organ Transplant Recipients: Evaluation of Risk in the National COVID Cohort Collaborative (N3C).
实体器官移植受者中 COVID-19 急性后遗症的患病率:国家 COVID 队列协作组织 (N3C) 的风险评估。
  • DOI:
    10.1016/j.ajt.2024.06.001
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    A. Vinson;Makayla Schissel;A. Anzalone;Ran Dai;E. French;A. Olex;Stephen B. Lee;Michael Ison;R. Mannon;A. Wilcox;Adam M. Lee;Alexis Graves;A. Anzalone;A. Manna;Amit Saha;A. Olex;Andrea Zhou;Andrew E. Williams;Andrew Southerland;A. Girvin;Anita Walden;Anjali A. Sharathkumar;B. Amor;Benjamin Bates;Brian Hendricks;Brijesh Patel;Caleb Alexander;Carolyn T Bramante;C. Ward‐Caviness;C. Madlock;Christine Suver;C. Chute;Christopher Dillon;Chunlei Wu;Clare Schmitt;Cliff Takemoto;D. Housman;D. Gabriel;David A. Eichmann;Diego Mazzotti;Don Brown;Eilis Boudreau;Elaine Hill;Elizabeth Zampino;E. Marti;Emily Pfaff;E. French;F. Koraishy;Federico Mariona;Fred Prior;G. Sokos;Greg Martin;H. Lehmann;Heidi Spratt;Hemalkumar Mehta;Hongfang Liu;Hythem Sidky;J. Hayanga;Jami D. Pincavitch;Jaylyn F. Clark;Jeremy Harper;Jessica Islam;Jin Ge;J. Gagnier;J. Saltz;J. Saltz;Johanna J. Loomba;Jon D. Buse;Jomol P Mathew;J. Rutter;J. McMurry;Justin Guinney;J. Starren;Kay Crowley;K. Bradwell;Kellie M. Walters;K. Wilkins;Kenneth R. Gersing;K. Cato;Kimberly Murray;K. Kostka;Lavance Northington;Lee A. Pyles;Leonie Misquitta;Lesley Cottrell;L. Portilla;Mariam Deacy;Mark Bissell;M. Clark;M. Emmett;M. Saltz;M. Palchuk;Melissa A. Haendel;Meredith Adams;Meredith Temple;Michael G. Kurilla;Michele Morris;N. Qureshi;Nasia Safdar;Nicole Garbarini;Noha Sharafeldin;O. Sadan;P. A. Francis;P. W. Burgoon;Peter Robinson;Philip R. O. Payne;Rafael Fuentes;R. Jawa;Rebecca Erwin;Rena C Patel;Richard A. Moffitt;R. Zhu;R. Kamaleswaran;R. Hurley;Robert T. Miller;S. Pyarajan;Sam G. Michael;Samuel Bozzette;Sandeep K Mallipattu;Satyanarayana Vedula;Scott A. Chapman;Shawn T O'Neil;Soko Setoguchi;Stephanie S. Hong;Steve Johnson;Tellen D. Bennett;Tiffany J. Callahan;Umit Topaloglu;Usman Sheikh;Valery Gordon;V. Subbian;Warren Kibbe;Wenndy Hernandez;Willarene P. Beasley;W. Cooper;W. Hillegass;X. Zhang
  • 通讯作者:
    X. Zhang

Sandeep K Mallipattu的其他文献

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{{ truncateString('Sandeep K Mallipattu', 18)}}的其他基金

Single-cell Cyclic Multiplex in Situ Tagging to Advance Kidney Research
单细胞循环多重原位标记促进肾脏研究
  • 批准号:
    10790122
  • 财政年份:
    2023
  • 资助金额:
    $ 36.11万
  • 项目类别:
Small Molecule KLF15 Agonists for Kidney Disease
治疗肾脏疾病的小分子 KLF15 激动剂
  • 批准号:
    10553107
  • 财政年份:
    2021
  • 资助金额:
    $ 36.11万
  • 项目类别:
Small Molecule KLF15 Agonists for Kidney Disease
治疗肾脏疾病的小分子 KLF15 激动剂
  • 批准号:
    10117332
  • 财政年份:
    2021
  • 资助金额:
    $ 36.11万
  • 项目类别:
Small Molecule KLF15 Agonists for Kidney Disease
治疗肾脏疾病的小分子 KLF15 激动剂
  • 批准号:
    10359057
  • 财政年份:
    2021
  • 资助金额:
    $ 36.11万
  • 项目类别:
ShEEP Request for High-throughput Single Cell Genomics Instrumentation
ShEEP 请求高通量单细胞基因组学仪器
  • 批准号:
    9795153
  • 财政年份:
    2019
  • 资助金额:
    $ 36.11万
  • 项目类别:
Role of KLF15 in proximal tubule metabolism
KLF15 在近曲小管代谢中的作用
  • 批准号:
    10481366
  • 财政年份:
    2018
  • 资助金额:
    $ 36.11万
  • 项目类别:
Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease
KLF6 在糖尿病肾病中对线粒体功能的转录控制
  • 批准号:
    10400042
  • 财政年份:
    2017
  • 资助金额:
    $ 36.11万
  • 项目类别:
Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease
KLF6 在糖尿病肾病中对线粒体功能的转录控制
  • 批准号:
    9918361
  • 财政年份:
    2017
  • 资助金额:
    $ 36.11万
  • 项目类别:
The Role of KLF15 as a transcriptional regulator of podocyte differentiation
KLF15 作为足细胞分化转录调节因子的作用
  • 批准号:
    8750137
  • 财政年份:
    2014
  • 资助金额:
    $ 36.11万
  • 项目类别:
The Role of KLF15 as a transcriptional regulator of podocyte differentiation
KLF15 作为足细胞分化转录调节因子的作用
  • 批准号:
    8916713
  • 财政年份:
    2014
  • 资助金额:
    $ 36.11万
  • 项目类别:

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