@article{c1bb6f38800a4120bc56909149e08a9e,
title = "APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R",
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.",
author = "Koji Okamoto and Rausch, {Jason W.} and Hidefumi Wakashin and Yulong Fu and Chung, {Joon Yong} and Dummer, {Patrick D.} and Shin, {Myung K.} and Preeti Chandra and Kosuke Suzuki and Shashi Shrivastav and Rosenberg, {Avi Z.} and Hewitt, {Stephen M.} and Ray, {Patricio E.} and Eisei Noiri and {Le Grice}, {Stuart F.J.} and Maarten Hoek and Zhe Han and Winkler, {Cheryl A.} and Kopp, {Jeffrey B.}",
note = "Funding Information: This work was supported in part by the Intramural Research Programs of the NIDDK and the National Cancer Institute, Center for Cancer Research, NIH. It was also funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E, NIH R01 grant DK115968 to P.E.R & Z.H., and NIH R01 grant DK098410 to Z.H. The salary of Y.F. was supported by NIH R01 grant DK103564 (P.E.R). We wish to acknowledge assistance from Dr. David Victor, NCI with DNA sequencing, Dr. Dominic Esposito, NCI with generation of expression vectors, and Huiyan Lu, NIDDK, with generation of transgenic mice. The authors appreciate helpful comments from Dr. Jurgen Heymann. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Publisher Copyright: {\textcopyright} 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s42003-018-0188-2",
language = "English",
volume = "1",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "Springer Nature",
number = "1",
}