Kruppel-like factor 6 regulates mitochondrial function in the kidney
Kruppel-like factor 6 regulates mitochondrial function in the kidney
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DOI：
10.1172/jci77084
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发表时间：
2015-03-01
影响因子：
15.9
通讯作者：
He, John C.
中科院分区：
文献类型：
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作者：
Mallipattu, Sandeep K.;Horne, Sylvia J.;He, John C.
线粒体结构和功能的维持对于预防肾脏中足细胞凋亡和最终肾小球硬化至关重要;然而，在足细胞损伤中调节线粒体功能的转录因子仍有待鉴定。在这里，我们确定Kruppel样因子6（KLF 6），锌指结构域转录因子，作为一个重要的调节器的线粒体功能的足细胞凋亡。我们观察到足细胞特异性Klf 6缺失增加了耐药小鼠品系对阿霉素诱导的局灶节段性肾小球硬化（FSGS）的易感性。KLF 6的表达诱导早期ADR在小鼠和培养的人足细胞，并防止线粒体功能障碍和激活这些足细胞的内在凋亡途径。启动子分析和染色质免疫沉淀研究表明，推定的KLF 6转录结合位点存在于线粒体细胞色素c氧化酶组装基因（SCO 2）的启动子中，这对于防止细胞色素c释放和激活内在凋亡途径至关重要。此外，HIV-1转基因小鼠的足细胞以及HIV相关肾病（HIVAN）和FSGS患者的肾活检组织中KLF 6表达减少。总之，这些研究结果表明，KLF 6依赖的细胞色素c氧化酶组装基因的调节是至关重要的维持线粒体功能和防止足细胞凋亡。
Maintenance of mitochondrial structure and function is critical for preventing podocyte apoptosis and eventual glomerulosclerosis in the kidney; however, the transcription factors that regulate mitochondrial function in podocyte injury remain to be identified. Here, we identified Kruppel-like factor 6 (KLF6), a zinc finger domain transcription factor, as an essential regulator of mitochondrial function in podocyte apoptosis. We observed that podocyte-specific deletion of Klf6 increased the susceptibility of a resistant mouse strain to adriamycin-induced (ADR-induced) focal segmental glomerulosclerosis (FSGS). KLF6 expression was induced early in response to ADR in mice and cultured human podocytes, and prevented mitochondrial dysfunction and activation of intrinsic apoptotic pathways in these podocytes. Promoter analysis and chromatin immunoprecipitation studies revealed that putative KLF6 transcriptional binding sites are present in the promoter of the mitochondrial cytochrome c oxidase assembly gene (SCO2), which is critical for preventing cytochrome c release and activation of the intrinsic apoptotic pathway. Additionally, KLF6 expression was reduced in podocytes from HIV-1 transgenic mice as well as in renal biopsies from patients with HIV-associated nephropathy (HIVAN) and FSGS. Together, these findings indicate that KLF6-dependent regulation of the cytochrome c oxidase assembly gene is critical for maintaining mitochondrial function and preventing podocyte apoptosis.