title: Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.
abstract: 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.
authors.affiliation: 1] Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA [2] Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Nichols
authors.affiliation: 1] Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA [2] Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Jog
authors.affiliation: 1] Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA [2] Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: 1] Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA [2] Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Blackler
authors.affiliation: 1] Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA [2] Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wilmot
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Glen
authors.initials: G
authors.lastname: Markowitz
authors.affiliation: Kidney Diseases Branch, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.affiliation: 1] Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
authors.affiliation: 1] Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA [2] Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Friedman
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000595:Amino Acid Sequence; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012307:Risk Factors; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3
references.citation: J Biol Chem. 2009 May 22;284(21):14136-46
references.pmid: 19307177
references.citation: Mol Cell. 2006 Jun 9;22(5):561-9
references.pmid: 16762830
references.citation: Genomics. 2001 May 15;74(1):71-8
references.pmid: 11374903
references.citation: Kidney Int. 2013 Dec;84(6):1207-13
references.pmid: 23677244
references.citation: J Am Soc Nephrol. 2006 Oct;17(10):2854-63
references.pmid: 16914539
references.citation: J Am Soc Nephrol. 2011 Nov;22(11):2119-28
references.pmid: 21997392
references.citation: J Biol Chem. 1998 Jul 10;273(28):17742-8
references.pmid: 9651374
references.citation: J Am Soc Nephrol. 2011 Nov;22(11):2098-105
references.pmid: 21997396
references.citation: Genomics. 2002 Apr;79(4):539-46
references.pmid: 11944986
references.citation: J Am Soc Nephrol. 2011 Nov;22(11):2129-37
references.pmid: 21997394
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D56-63
references.pmid: 23193274
references.citation: J Am Soc Nephrol. 2013 Apr;24(5):722-5
references.pmid: 23520206
references.citation: Science. 2010 Aug 13;329(5993):841-5
references.pmid: 20647424
references.citation: J Biol Chem. 1997 Oct 10;272(41):25576-82
references.pmid: 9325276
references.citation: Hum Genet. 2010 Sep;128(3):345-50
references.pmid: 20635188
references.citation: Nat Med. 2013 Mar;19(3):313-21
references.pmid: 23396211
references.citation: PLoS One. 2012;7(12):e51546
references.pmid: 23300552
references.citation: Nature. 2003 Mar 6;422(6927):83-7
references.pmid: 12621437
references.citation: J Clin Invest. 2011 Sep;121(9):3367-74
references.pmid: 21881214
references.citation: Arthritis Rheumatol. 2014 Feb;66(2):390-6
references.pmid: 24504811
references.citation: Nat Immunol. 2010 May;11(5):373-84
references.pmid: 20404851
references.citation: Cell. 2010 May 14;141(4):668-81
references.pmid: 20451243
references.citation: Autophagy. 2008 Nov;4(8):1079-82
references.pmid: 18927493
references.citation: Cell. 2009 Dec 24;139(7):1255-67
references.pmid: 20064372
references.citation: Clin J Am Soc Nephrol. 2010 Apr;5(4):607-15
references.pmid: 20203164
references.citation: Clin Cancer Res. 1999 Jun;5(6):1569-82
references.pmid: 10389946
references.citation: J Lipid Res. 2001 Apr;42(4):620-30
references.pmid: 11290834
references.citation: Nat Rev Drug Discov. 2011 Feb;10(2):127-40
references.pmid: 21283107
references.citation: Curr Opin Organ Transplant. 2011 Dec;16(6):614-9
references.pmid: 21971513
references.citation: Nephrol Dial Transplant. 2012 Jan;27(1):81-9
references.pmid: 21617192
references.citation: J Immunol. 2004 Feb 1;172(3):1699-710
references.pmid: 14734752
references.citation: Immunity. 2008 Jul 18;29(1):12-20
references.pmid: 18631453
references.citation: Genome Res. 2009 May;19(5):850-8
references.pmid: 19299565
references.citation: N Engl J Med. 2006 Dec 28;355(26):2752-6
references.pmid: 17192540