Scientific Publications

Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.

Publication TypeJournal Article
AuthorsNichols, B., Jog P., Lee JH, Blackler D., Wilmot M., D'Agati V., Markowitz G., Kopp JB, Alper SL, Pollak MR, and Friedman DJ
AbstractApolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and Toll-like receptor (TLR) agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IFN-regulatory factor 3 (IRF3)-dependent pathway. Using pharmacological inhibitors, small hairpin RNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-κB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that antiviral pathways may be important inducers of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment.Kidney International advance online publication, 6 August 2014; doi:10.1038/ki.2014.270.
Year of Publication2014
JournalKidney international
Date Published (YYYY/MM/DD)2014/08/06
ISSN Number0085-2538
DOI10.1038/ki.2014.270
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/25100047?dopt=Abstract