Krüppel-like factor 6 regulates mitochondrial function in the kidney

J Clin Invest. 2015 Mar 2;125(3):1347-61. doi: 10.1172/JCI77084. Epub 2015 Feb 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Binding Sites
  • Cells, Cultured
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Female
  • Glomerulosclerosis, Focal Segmental / metabolism*
  • Glomerulosclerosis, Focal Segmental / pathology
  • Glomerulosclerosis, Focal Segmental / virology
  • HIV Infections / complications*
  • HIV Infections / metabolism
  • HIV-1 / physiology
  • Humans
  • Kidney / metabolism*
  • Kidney / pathology
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors / physiology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / physiology*
  • Podocytes / physiology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / physiology*

Substances

  • Klf6 protein, mouse
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors
  • Proto-Oncogene Proteins
  • SCO2 protein, mouse
  • Electron Transport Complex IV