Krüppel-like factor 6 regulates mitochondrial function in the kidney
Sandeep K. Mallipattu, Sylvia J. Horne, Vivette D’Agati, Goutham Narla, Ruijie Liu, Michael A. Frohman, Kathleen Dickman, Edward Y. Chen, Avi Ma’ayan, Agnieszka B. Bialkowska, Amr M. Ghaleb, Mandayam O. Nandan, Mukesh K. Jain, Ilse Daehn, Peter Y. Chuang, Vincent W. Yang, John C. He
Sandeep K. Mallipattu, Sylvia J. Horne, Vivette D’Agati, Goutham Narla, Ruijie Liu, Michael A. Frohman, Kathleen Dickman, Edward Y. Chen, Avi Ma’ayan, Agnieszka B. Bialkowska, Amr M. Ghaleb, Mandayam O. Nandan, Mukesh K. Jain, Ilse Daehn, Peter Y. Chuang, Vincent W. Yang, John C. He
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Research Article

Krüppel-like factor 6 regulates mitochondrial function in the kidney

Abstract

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 Krüppel-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.

Authors

Sandeep K. Mallipattu, Sylvia J. Horne, Vivette D’Agati, Goutham Narla, Ruijie Liu, Michael A. Frohman, Kathleen Dickman, Edward Y. Chen, Avi Ma’ayan, Agnieszka B. Bialkowska, Amr M. Ghaleb, Mandayam O. Nandan, Mukesh K. Jain, Ilse Daehn, Peter Y. Chuang, Vincent W. Yang, John C. He

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Figure 7

KLF6 expression is increased early with ADR treatment.

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KLF6 expression is increased early with ADR treatment. Primary podocytes...
Primary podocytes isolated from WT mice were treated with and without ADR for 12 hours. RNA was extracted, and real-time PCR was performed. (A) Klf6 mRNA expression was compared between primary cultured murine podocytes treated with and without ADR (n = 5). Mann-Whitney U test, **P < 0.01. (B) This was confirmed by immunofluorescence using tissue from WT mice treated with and without ADR. Representative pictures of six mice in each group are shown in the top panel (original magnification, ×20). Bottom panel: 30 glomeruli per mouse were selected, and KLF6 expression was quantified in the glomerular region (n = 6). Unpaired t test, ***P < 0.001. (C) Cultured human podocytes were treated with ADR for 6, 12, 18, and 24 hours. Protein was extracted, and Western blot analysis was performed for KLF6. A representative blot of three independent experiments is shown in the top panel. Densitometry analysis is shown in the bottom panel (n = 6). Kruskal-Wallis test with Dunn’s post-hoc test, **P < 0.01 vs. untreated cells. (D) Immunofluorescence staining for KLF6 with and without ADR for 12 hours is shown. Representative images of six independent experiments are shown in the top panel (original magnification, ×20, scale bar: 100 μm). In the bottom panel, the intensity of KLF6 expression was quantified (n = 6). Unpaired t test, ***P < 0.001.