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Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1

Kidney international, 2015-02, Vol.87 (2), p.332-342 [Peer Reviewed Journal]

2015 International Society of Nephrology ;Copyright Nature Publishing Group Feb 2015 ;ISSN: 0085-2538 ;EISSN: 1523-1755 ;DOI: 10.1038/ki.2014.270 ;PMID: 25100047

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Title:
Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1
Author: Nichols, Brendan ; Jog, Prachi ; Lee, Jessica H. ; Blackler, Daniel ; Wilmot, Michael ; D'Agati, Vivette ; Markowitz, Glen ; Kopp, Jeffrey B. ; Alper, Seth L. ; Pollak, Martin R. ; Friedman, David J.
Subjects: Adult ; African Americans - genetics ; Aged ; Amino Acid Sequence ; Apolipoprotein L1 ; Apolipoproteins - genetics ; chronic kidney disease ; Cohort Studies ; expression ; Female ; focal segmental glomerulosclerosis ; gene ; Gene Expression Regulation ; Genotype ; Glomerulosclerosis, Focal Segmental - genetics ; Glomerulosclerosis, Focal Segmental - immunology ; HEK293 Cells ; Humans ; Immunity, Innate ; inflammation ; Lipoproteins, HDL - genetics ; Male ; Middle Aged ; Molecular Sequence Data ; Risk Factors ; Signal Transduction ; Toll-Like Receptor 3 - metabolism
Is Part Of: Kidney international, 2015-02, Vol.87 (2), p.332-342
Description: Apolipoprotein 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0085-2538
EISSN: 1523-1755
DOI: 10.1038/ki.2014.270
PMID: 25100047
Source: MEDLINE
Alma/SFX Local Collection
ProQuest Central

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Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1

2015 International Society of Nephrology ;Copyright Nature Publishing Group Feb 2015 ;ISSN: 0085-2538 ;EISSN: 1523-1755 ;DOI: 10.1038/ki.2014.270 ;PMID: 25100047

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