APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R

Koji Okamoto, Jason W. Rausch, Hidefumi Wakashin, Yulong Fu, Joon Yong Chung, Patrick D. Dummer, Myung K. Shin, Preeti Chandra, Kosuke Suzuki, Shashi Shrivastav, Avi Rosenberg, Stephen M. Hewitt, Patricio E. Ray, Eisei Noiri, Stuart F.J. Le Grice, Maarten Hoek, Zhe Han, Cheryl A. Winkler, Jeffrey B. Kopp

Research output: Contribution to journalArticle

Abstract

APOL1 risk alleles associate with chronic kidney disease in African Americans, but the mechanisms remain to be fully understood. We show that APOL1 risk alleles activate protein kinase R (PKR) in cultured cells and transgenic mice. This effect is preserved when a premature stop codon is introduced to APOL1 risk alleles, suggesting that APOL1 RNA but not protein is required for the effect. Podocyte expression of APOL1 risk allele RNA, but not protein, in transgenic mice induces glomerular injury and proteinuria. Structural analysis of the APOL1 RNA shows that the risk variants possess secondary structure serving as a scaffold for tandem PKR binding and activation. These findings provide a mechanism by which APOL1 variants damage podocytes and suggest novel therapeutic strategies.

Original languageEnglish (US)
Article number188
JournalCommunications Biology
Volume1
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

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    Okamoto, K., Rausch, J. W., Wakashin, H., Fu, Y., Chung, J. Y., Dummer, P. D., Shin, M. K., Chandra, P., Suzuki, K., Shrivastav, S., Rosenberg, A., Hewitt, S. M., Ray, P. E., Noiri, E., Le Grice, S. F. J., Hoek, M., Han, Z., Winkler, C. A., & Kopp, J. B. (2018). APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R. Communications Biology, 1(1), [188]. https://doi.org/10.1038/s42003-018-0188-2