Characterization of circulating APOL1 protein complexes in African Americans

Abstract

APOL1 gene renal-risk variants are associated with nephropathy and CVD in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from nonrisk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two nonoverlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter). Neither of these protein complexes associated with HDL or LDL. Proteomic analysis revealed that complex A was composed of APOA1, haptoglobin-related protein (HPR), and complement C3, whereas complex B contained APOA1, HPR, IgM, and fibronectin. Serum HPR was less abundant on complex B in individuals with G1 and G2 renal-risk variant genotypes, relative to G0 (P = 0.0002–0.037). These circulating complexes may play roles in HDL metabolism and susceptibility to CVD. APOL1 gene renal-risk variants are associated with nephropathy and CVD in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from nonrisk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two nonoverlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter). Neither of these protein complexes associated with HDL or LDL. Proteomic analysis revealed that complex A was composed of APOA1, haptoglobin-related protein (HPR), and complement C3, whereas complex B contained APOA1, HPR, IgM, and fibronectin. Serum HPR was less abundant on complex B in individuals with G1 and G2 renal-risk variant genotypes, relative to G0 (P = 0.0002–0.037). These circulating complexes may play roles in HDL metabolism and susceptibility to CVD. A major breakthrough in human molecular genetics was identification of the powerful contribution of APOL1 gene G1 and G2 renal-risk variants to nondiabetic nephropathy susceptibility in African Americans (1.Genovese G. Friedman D.J. Ross M.D. Lecordier L. Uzureau P. Freedman B.I. Bowden D.W. Langefeld C.D. Oleksyk T.K. Uscinski Knob A.L. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1401) Google Scholar). HIV-associated nephropathy, idiopathic focal segmental glomerulosclerosis, severe lupus nephritis, sickle cell nephropathy, and hypertension-attributed nephropathy strongly associate with APOL1 G1 and G2 renal-risk variants on chromosome 22q13.1 (1.Genovese G. Friedman D.J. Ross M.D. Lecordier L. Uzureau P. Freedman B.I. Bowden D.W. Langefeld C.D. Oleksyk T.K. Uscinski Knob A.L. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1401) Google Scholar, 2.Tzur S. Rosset S. Shemer R. Yudkovsky G. Selig S. Tarekegn A. Bekele E. Bradman N. Wasser W.G. Behar D.M. et al.Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.Hum. Genet. 2010; 128: 345-350Crossref PubMed Scopus (457) Google Scholar, 3.Freedman B.I. Kopp J.B. Langefeld C.D. Genovese G. Friedman D.J. Nelson G.W. Winkler C.A. Bowden D.W. Pollak M.R. The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans.J. Am. Soc. Nephrol. 2010; 21: 1422-1426Crossref PubMed Scopus (207) Google Scholar). Although APOL1 mRNA and APOL1 protein are present in human kidney (4.Madhavan S.M. O'Toole J.F. Konieczkowski M. Ganesan S. Bruggeman L.A. Sedor J.R. APOL1 localization in normal kidney and nondiabetic kidney disease.J. Am. Soc. Nephrol. 2011; 22: 2119-2128Crossref PubMed Scopus (190) Google Scholar, 5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar), the major APOL1 reservoir appears to be circulating protein (5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar, 6.Duchateau P.N. Pullinger C.R. Orellana R.E. Kunitake S.T. Naya-Vigne J. O'Connor P.M. Malloy M.J. Kane J.P. Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L.J. Biol. Chem. 1997; 272: 25576-25582Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). APOL1 was initially discovered as a minor apolipoprotein of plasma HDLs (6.Duchateau P.N. Pullinger C.R. Orellana R.E. Kunitake S.T. Naya-Vigne J. O'Connor P.M. Malloy M.J. Kane J.P. Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L.J. Biol. Chem. 1997; 272: 25576-25582Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar); however, its distribution among HDL subfractions has not been well-defined. APOL1 nephropathy variants associate with HDL subfraction concentrations (7.Gutierrez O.M. Judd S.E. Irvin M.R. Zhi D. Limdi N. Palmer N.D. Rich S.S. Sale M.M. Freedman B.I. APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans.Nephrol. Dial. Transplant. 2015; 272Google Scholar) and CVD risk, although controversial results have been reported with CVD (8.Ito K. Bick A.G. Flannick J. Friedman D.J. Genovese G. Parfenov M.G. Depalma S.R. Gupta N. Gabriel S.B. Taylor H.A. et al.Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.Circ. Res. 2014; 114: 845-850Crossref PubMed Scopus (120) Google Scholar, 9.Detrano R. Guerci A.D. Carr J.J. Bild D.E. Burke G. Folsom A.R. Liu K. Shea S. Szklo M. Bluemke D.A. et al.Coronary calcium as a predictor of coronary events in four racial or ethnic groups.N. Engl. J. Med. 2008; 358: 1336-1345Crossref PubMed Scopus (2121) Google Scholar, 10.Langefeld C.D. Divers J. Pajewski N.M. Hawfield A.T. Reboussin D.M. Bild D.E. Kaysen G.A. Kimmel P.L. Raj D.S. Ricardo A.C. et al.Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial.Kidney Int. 2015; 87: 169-175Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 11.Freedman B.I. Langefeld C.D. Lu L. Palmer N.D. Smith S.C. Bagwell B.M. Hicks P.J. Xu J. Wagenknecht L.E. Raffield L.M. et al.APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes.Kidney Int. 2015; 87: 176-181Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Trypanosome lytic factors (TLF1 and TLF2) contain APOL1 protein (12.Uzureau P. Uzureau S. Lecordier L. Fontaine F. Tebabi P. Homble F. Grelard A. Zhendre V. Nolan D.P. Lins L. et al.Mechanism of Trypanosoma brucei gambiense resistance to human serum.Nature. 2013; 501: 430-434Crossref PubMed Scopus (114) Google Scholar) and are minor HDL subfractions in humans that contribute to innate immunity via protection from infection, including from African trypanosomes (13.Samanovic M. Molina-Portela M.P. Chessler A.D. Burleigh B.A. Raper J. Trypanosome lytic factor, an antimicrobial high-density lipoprotein, ameliorates Leishmania infection.PLoS Pathog. 2009; 5: e1000276Crossref PubMed Scopus (62) Google Scholar). Association was not observed between plasma APOL1 concentrations and APOL1 genotype in African Americans with treated HIV infection; plasma APOL1 levels also did not associate with the risk of HIV-associated nephropathy or chronic kidney disease (14.Bruggeman L.A. O'Toole J.F. Ross M.D. Madhavan S.M. Smurzynski M. Wu K. Bosch R.J. Gupta S. Pollak M.R. Sedor J.R. et al.Plasma apolipoprotein L1 levels do not correlate with CKD.J. Am. Soc. Nephrol. 2014; 25: 634-644Crossref PubMed Scopus (77) Google Scholar). Whether serum APOL1 protein levels and their distribution among HDL particles are associated with APOL1 genotypes in healthy individuals is unknown. Because free APOL1 protein may be taken up by podocytes in vitro (5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar), it remains critical to determine whether serum APOL1 concentrations or the structure/composition of variant APOL1 proteins and their associated complexes are specific to the G1 and G2 renal-risk variants, relative to nonrisk G0. To address these issues, serum APOL1 protein levels and size distribution were examined in age- and gender-matched African Americans without kidney disease based on APOL1 genotype using fast protein LC (FPLC) and analysis was to the of APOL1 These results on APOL1 circulating APOL1 protein and complexes in human CVD and HDL healthy African Americans without nephropathy and were from of These with nondiabetic of kidney was in and in Serum was in and in and were in and were not observed or kidney with to APOL1 genotype. The the of the and of the are in APOL1 levels and by APOL1 genotype in African without kidney were by the APOL1 were serum and to the of from normal The serum by APOL1 genotype was are as the in a new were by the APOL1 were serum and to the of from normal The serum by APOL1 genotype was are as the of from the was by a and with and were with a were in and in with were using and on were and using a an protein protein previously in D. A. L. Murea M. Freedman B.I. Shelness G.S. and of APOL1 renal-risk variant proteins in and Res. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar) was of from four healthy individuals APOL1 four and four G2 variants were a were a of A was to distribution among from to nm or to as by were by and with and as of from four healthy individuals APOL1 four and four G2 variants was in and to were in and primary were with were with with or 2 and with was and were using a of plasma from four healthy individuals APOL1 four and four G2 variants were to a of with of normal and to = with were with an = and in a and were and were with and to by APOL1 and as of plasma was on 2 were to a by 2 were with and with or were with with or 2 and with was and were using a from four healthy individuals APOL1 four and four G2 variants was a were a of A was to distributions among complex B and complex A were with of were to of APOL1 complex A and complex B of which were a and and The was in The primary was and the was APOL1 protein was as previously reported (5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar, D. A. L. Murea M. Freedman B.I. Shelness G.S. and of APOL1 renal-risk variant proteins in and Res. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). to APOL1 of the APOL1 was by and the to a protein in A protein was in a was with a to the of complex A and of complex B APOL1 by were to with in a was The was by on a was of protein A The was 2 the and the using was to the The was the were and the analysis with protein and of APOL1 complexes in complex A and B the were by and were with were from the and to was with and by using in were from the and on a to a high LC were as A and B were a 2 with a of of A using an 2 with a of B and a of The were were to the via with the The was in using were the of a of were using of and in the were and using with the and the human two a of and of and were as of proteins the complex were a of Serum from age- and with nondiabetic kidney disease were by to determine whether circulating APOL1 concentrations were associated with APOL1 renal-risk variant genotypes in African Americans without kidney and in genotype and were with (6.Duchateau P.N. Pullinger C.R. Orellana R.E. Kunitake S.T. Naya-Vigne J. O'Connor P.M. Malloy M.J. Kane J.P. Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L.J. Biol. Chem. 1997; 272: 25576-25582Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar), two were the two APOL1 and present in the Although APOL1 concentrations among were of APOL1 serum APOL1 concentrations were with an protein of known serum APOL1 concentrations genotype are in To in size distribution among and were on serum from African Americans nephropathy with APOL1 renal-risk variant and the of particles to between and of genotype The was nm in molecular with a the nm molecular serum APOL1 protein was in the of the and A. M.J. P.L. of HDL by results in to with Biol. PubMed Scopus Google Scholar) These results that serum APOL1 is on particles serum HDL and LDL. Serum were by lipoprotein was by and were by to lipoprotein APOL1 in between the and HDL to a with particles to these as APOL1 complex A and complex to the and particles using To determine whether complexes were bound to HDL or density = was using from healthy African Americans with APOL1 on of APOL1 protein was in the whereas of was in the that APOL1 was not as strongly associated with HDL as was of APOL1 genotype. or of high did not the of that APOL1 was in a complex that did not contain to was that by to determine whether APOL1 with HDL. Serum APOL1 in the of APOA1, and not in the HDL particles also that serum APOL1 is not bound to HDL analysis of serum by that APOL1 in complexes A and B similar size distributions as in serum that was not to results using lipoprotein that on and the that APOL1 is a of complexes similar in size to HDL and To determine whether was a in the size of these complexes in African Americans with APOL1 genotypes, a of was by serum from individuals with APOL1 genotypes and = 2 APOL1 of that complex A nm diameter) was composed of size as complexes and whereas a was complex B nm diameter) complex A and complex B were by based on A with as and from to and complex B as were from protein identification via The size of complex A and by were with and on the these complexes are referred to as and 2 the proteins that were by from complex A and complex B and in healthy African of APOL1 complex A and complex B using a the of APOL1 was using serum from African Americans with APOL1 genotypes and = The were examined by analysis using proteins that were by HPR, and on complex A and complex however, complement was to APOL1 complex A as a on APOL1 complex B in to R. Genovese G. D. M. Winkler C.A. Kopp J. A. et of the trypanolytic 2014; PubMed Scopus Google Scholar). The in 2 were not their to the of via between of APOL1 with and that with the of to on APOL1 complexes have been in human by with of of on APOL1 complexes A and B by proteins that were via proteins that were via proteins that were via proteins that were via proteins that were via proteins that were via proteins that were via protein proteins that were via proteins are present in and complexes A and B from proteins that were via in a new proteins are present in and complexes A and B from APOL1 protein concentrations in complex A and complex B were in African Americans with APOL1 and genotypes = via a of known concentrations of protein using previously (5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar). complex B of APOL1 were with HPR a of HPR was less abundant on complex B in individuals with APOL1 and genotypes, relative to with genotypes was observed on complex A in individuals with APOL1 The distribution was with that of APOL1 was present on protein whereas was in the APOL1 APOL1 were observed in APOL1 distributions with of APOL1 To between APOL1 and renal-risk variants, the of APOL1 to APOL1 was on complex B from healthy African Americans with APOL1 from the individuals APOL1 were by analysis was using an APOL1 was in complex B from with APOL1 or variants relative to among APOL1 genotypes were also examined in complex however, were observed not between circulating APOL1 G0 and G1 and G2 renal-risk variant proteins were in an to roles in human APOL1 is present in the and to a in the and including the APOL1 protein is in relative to and (5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar). to the of APOL1 in human serum and of free APOL1 podocytes in vitro (5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar), it was initially that circulating APOL1 protein contribute to nephropathy. kidney to J.A. Murea M. P.L. Langefeld C.D. Bowden D.W. Hicks P.J. R.J. et APOL1 gene and kidney J. Transplant. 2011; PubMed Scopus Google Scholar, V. R. A. S. Genovese G. Ross M.D. Friedman D.J. et APOL1 genotype of African kidney not J. Transplant. PubMed Scopus Google Scholar, B.I. B.A. D. M.D. V. A.D. et al.Apolipoprotein L1 gene variants in are associated with J. Transplant. 2015; PubMed Scopus Google Scholar); however, roles circulating APOL1 protein in CVD and metabolism (7.Gutierrez O.M. Judd S.E. Irvin M.R. Zhi D. Limdi N. Palmer N.D. Rich S.S. Sale M.M. Freedman B.I. APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans.Nephrol. Dial. Transplant. 2015; 272Google Scholar). was observed between APOL1 G1 and G2 risk variant genotypes and serum APOL1 by in African Americans kidney renal-risk variant genotype and with healthy individuals of similar and distributions in We the of to a in serum APOL1 protein in = with two APOL1 renal-risk or in serum These results the of Bruggeman et (14.Bruggeman L.A. O'Toole J.F. Ross M.D. Madhavan S.M. Smurzynski M. Wu K. Bosch R.J. Gupta S. Pollak M.R. Sedor J.R. et al.Plasma apolipoprotein L1 levels do not correlate with CKD.J. Am. Soc. Nephrol. 2014; 25: 634-644Crossref PubMed Scopus (77) Google Scholar) in African Americans with HIV serum APOL1 protein concentrations are genotype it appears that risk disease may to protein (14.Bruggeman L.A. O'Toole J.F. Ross M.D. Madhavan S.M. Smurzynski M. Wu K. Bosch R.J. Gupta S. Pollak M.R. Sedor J.R. et al.Plasma apolipoprotein L1 levels do not correlate with CKD.J. Am. Soc. Nephrol. 2014; 25: 634-644Crossref PubMed Scopus (77) Google Scholar). The size distribution of particles in human relative to HDL and was using is less to HDL distribution A.C. of on apolipoprotein lipoprotein Res. Full Text PDF PubMed Google Scholar, S.T. Kane J.P. the of high density in the Res. Full Text PDF PubMed Google Scholar). particles were present in two major protein APOL1 complex A nm and APOL1 complex B nm were with on using APOL1 complex A is HDL particles with similar distributions APOL1 and density of plasma to = plasma lipoprotein R.J. H.A. The distribution and of in human PubMed Scopus Google Scholar), of APOL1 and to with as APOA1, which was it been that particles were a of HDL (6.Duchateau P.N. Pullinger C.R. Orellana R.E. Kunitake S.T. Naya-Vigne J. O'Connor P.M. Malloy M.J. Kane J.P. Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L.J. Biol. Chem. 1997; 272: 25576-25582Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). were not in complex A or complex however, are to be in the density density a density = in a by et R. Genovese G. D. M. Winkler C.A. Kopp J. A. et of the trypanolytic 2014; PubMed Scopus Google Scholar). did not as the of APOL1 in and unknown. revealed that APOL1 not to the of serum HDL by its the with HDL that the is with that APOL1 has a size distribution and that APOL1 is not associated with normal size HDL particles on the results from complexes do not to in serum HDL as by and have that a of plasma HDL particles are in size nm diameter) plasma and in the on These are HDL particles by or of plasma HDL by or proteins J.P. Malloy M.J. HDL and coronary PubMed Scopus Google Scholar, and its in HDL PubMed Scopus Google Scholar, V. J. M. D.J. et and the of PubMed Scopus Google Scholar). to complexes proteins in innate immunity J.J. protein in human plasma with proteins to immunity and 2010; PubMed Scopus Google Scholar), that HDL be as complexes in innate Proteomic were to in the of APOL1 complex A and complex B in healthy African Americans with APOL1 and of complexes A and B were to and to complexes by and was an to the of proteins by and of results the that circulating APOL1 complexes are to be the previously and based on complex size (13.Samanovic M. Molina-Portela M.P. Chessler A.D. Burleigh B.A. Raper J. Trypanosome lytic factor, an antimicrobial high-density lipoprotein, ameliorates Leishmania infection.PLoS Pathog. 2009; 5: e1000276Crossref PubMed Scopus (62) Google Scholar) and APOL1 and profiles of APOL1 that APOL1 and in serum protein HPR is a of based on its to HPR is as a protein that is to an and a which via a M.J. D. protein is a plasma PubMed Scopus Google Scholar). The is a HPR that its J. R. J. V. S. of a lytic from human PubMed Google Scholar, M. P. M.R. Raper J. of lytic PubMed Scopus Google Scholar). Because and HPR are highly HPR and The size between and or is the to the by the HPR M.J. D. protein is a plasma PubMed Scopus Google Scholar), which the of the The trypanolytic R. Genovese G. D. M. Winkler C.A. Kopp J. A. et of the trypanolytic 2014; PubMed Scopus Google Scholar) is with APOL1 distribution The of and HPR in complex A is with that of J. R. J. V. S. of a lytic from human PubMed Google Scholar) and the of APOA1, HPR, and is with that of J. R. J. V. S. of a lytic from human PubMed Google Scholar). APOL1 complexes A and B contain APOA1, and complexes were in complex A or in complex B or APOL1 is the that the G1 and G2 renal-risk variants E. B. L. F. Nolan D.P. D. The trypanolytic of human PubMed Scopus Google Scholar). the also to be altered in the between the and to APOL1 the variants was observed We that the APOL1 complex B in individuals with the G1 or G2 variant of APOL1 of in that on the of the protein the of on complex B in individuals with G1 or G2 variants may its to although the G1 and G2 variants are (1.Genovese G. Friedman D.J. Ross M.D. Lecordier L. Uzureau P. Freedman B.I. Bowden D.W. Langefeld C.D. Oleksyk T.K. Uscinski Knob A.L. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1401) Google Scholar). on APOL1 and serum distribution serum APOL1 with We not determine whether serum APOL1 is with HPR HPR do not and specific of HPR and are from the and their are in HPR and proteins are present in kidney appears that APOL1 protein in podocytes is (4.Madhavan S.M. O'Toole J.F. Konieczkowski M. Ganesan S. Bruggeman L.A. Sedor J.R. APOL1 localization in normal kidney and nondiabetic kidney disease.J. Am. Soc. Nephrol. 2011; 22: 2119-2128Crossref PubMed Scopus (190) Google Scholar, 5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar). A of HDL is in the kidney in human and K. of the the of high density lipoprotein in the African Res. Full Text Full Text PDF PubMed Google Scholar, A. Smith P.L. HDLs in are in plasma but are by the Res. Full Text Full Text PDF PubMed Scopus Google Scholar). APOL1 (5.Ma L. Shelness G.S. Snipes J.A. Murea M. Antinozzi P.A. Cheng D. Saleem M.A. Satchell S.C. Banas B. Mathieson P.W. et al.Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J. Am. Soc. Nephrol. 2015; 26: 339-348Crossref PubMed Scopus (96) Google Scholar), APOA1, and HPR proteins are present in cells, but not whereas HPR and are in not is that circulating APOL1 are by G. P. L. N. A. A. R. M. L. et is a of apolipoprotein Int. 2015; 87: Full Text Full Text PDF PubMed Scopus Google Scholar), of in glomerulosclerosis, as Although results do not a the APOL1 complexes in the of to the of and HPR and the of APOL1 complexes (TLF1 and in the that APOL1 in the in is the major of focal We that the of circulating APOL1 in the of which not HDL APOL1 G1 and G2 renal-risk variant genotypes to the and the of these roles in complexes in human disease and susceptibility to the of with fast protein LC haptoglobin-related protein protein of and lytic