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APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R
- Source :
- Communications Biology, Communications Biology, Vol 1, Iss 1, Pp 1-12 (2018)
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group UK, 2018.
-
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.<br />Okamoto et al. report that APOL1 RNA, but not protein, expressed from chronic kidney disease (CKD)-associated alleles activates protein kinase R, inducing glomerular injury in a mouse model. The secondary structure of APOL1 risk variant RNA acts as a scaffold for protein kinase R, suggesting potential therapeutic strategies for CKD.
- Subjects :
- 0301 basic medicine
Genetically modified mouse
030232 urology & nephrology
Medicine (miscellaneous)
Biology
urologic and male genital diseases
General Biochemistry, Genetics and Molecular Biology
Article
Podocyte
03 medical and health sciences
0302 clinical medicine
medicine
lcsh:QH301-705.5
Protein secondary structure
Proteinuria
RNA
medicine.disease
Protein kinase R
female genital diseases and pregnancy complications
030104 developmental biology
medicine.anatomical_structure
lcsh:Biology (General)
Toxicity
Cancer research
medicine.symptom
General Agricultural and Biological Sciences
Kidney disease
Subjects
Details
- Language :
- English
- ISSN :
- 23993642
- Volume :
- 1
- Database :
- OpenAIRE
- Journal :
- Communications Biology
- Accession number :
- edsair.doi.dedup.....3a51a58fada663e70976224c76ce42ca