Krüppel-like factor 6 regulates mitochondrial function in the kidney
Sandeep K. Mallipattu, … , Vincent W. Yang, John C. He
Sandeep K. Mallipattu, … , Vincent W. Yang, John C. He
Published February 17, 2015
Citation Information: J Clin Invest. 2015;125(3):1347-1361. https://doi.org/10.1172/JCI77084.
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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 11

Reduced KLF6 expression in human HIVAN and FSGS.

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Reduced KLF6 expression in human HIVAN and FSGS. (A) Immunostaining for ...
(A) Immunostaining for KLF6 performed on healthy donor nephrectomy specimens shows a nuclear distribution in podocytes and parietal cells, with a nuclear and cytosolic distribution in tubular cells. By immunohistochemistry, KLF6 expression in the podocytes (arrows) is shown in the biopsy specimens from healthy donors and in patients with diagnosed HIVAN and idiopathic noncollapsing FSGS. Representative images of six subjects in each group are shown (original magnification, ×20). (B) Immunofluorescence was performed using WT1 (podocyte-specific marker) to colocalize for podocyte-specific KLF6 expression in renal biopsy specimens from 10 healthy donor nephrectomies and in 10 patients with idiopathic noncollapsing FSGS. Representative images from 10 subjects in each group are shown (original magnification, ×20). Arrows show colocalization of KLF6 to WT1. Arrowheads show a lack of colocalization of KLF6 to WT1. (C) Twenty glomeruli per biopsy specimen were selected, and quantification of KLF6 staining in the podocytes was determined as the ratio of KLF6+WT1+ cells to WT1+ cells (n = 10). Mann-Whitney U test, ***P < 0.001.