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• W3152090481 abstract "APOL1 kidney risk variants (RVs) were identified in 2010 as major drivers of glomerular, tubulointerstitial, and renal microvascular disease in individuals with sub-Saharan African ancestry. In December 2020, the “APOL1 at Ten” conference summarized the first decade of progress and discussed controversies and uncertainties that remain to be addressed. Topics included trypanosome infection and its role in the evolution of APOL1 kidney RVs, clinical phenotypes in APOL1-associated nephropathy, relationships between APOL1 RVs and background haplotypes on cell injury and molecular mechanisms initiating disease, the role of clinical APOL1 genotyping, and development of novel therapies for kidney disease. Future goals were defined, including improved characterization of various APOL1 RV phenotypes in patients and experimental preclinical models; further dissection of APOL1-mediated pathways to cellular injury and dysfunction in kidney (and other) cells; clarification of gene-gene and gene-environment interactions; and evaluation of the role for existing and novel therapies. APOL1 kidney risk variants (RVs) were identified in 2010 as major drivers of glomerular, tubulointerstitial, and renal microvascular disease in individuals with sub-Saharan African ancestry. In December 2020, the “APOL1 at Ten” conference summarized the first decade of progress and discussed controversies and uncertainties that remain to be addressed. Topics included trypanosome infection and its role in the evolution of APOL1 kidney RVs, clinical phenotypes in APOL1-associated nephropathy, relationships between APOL1 RVs and background haplotypes on cell injury and molecular mechanisms initiating disease, the role of clinical APOL1 genotyping, and development of novel therapies for kidney disease. Future goals were defined, including improved characterization of various APOL1 RV phenotypes in patients and experimental preclinical models; further dissection of APOL1-mediated pathways to cellular injury and dysfunction in kidney (and other) cells; clarification of gene-gene and gene-environment interactions; and evaluation of the role for existing and novel therapies. Trypanosoma are unicellular parasitic protozoa. Trypanosoma brucei species cause potentially fatal human sleeping sickness as they move between the mammalian host and the tsetse fly. Human blood contains trypanolytic factors, composed of haptoglobin-related protein, apolipoprotein L1 (APOL1), apolipoprotein A1 (APOA-1), and IgM.1Lugli E.B. Pouliot M. Portela Mdel P. et al.Characterization of primate trypanosome lytic factors.Mol Biochem Parasitol. 2004; 138: 9-20Crossref PubMed Scopus (66) Google Scholar APOL1 is the main lethal factor in the trypanolytic factor. After endocytosis of the trypanolytic factor by trypanosomes, APOL1 is activated by a 2-step process: activation at acidic pH followed by channel opening at neutral pH.2Thomson R. Finkelstein A. Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: relevance to trypanosome lysis.Proc Natl Acad Sci U S A. 2015; 112: 2894-2899Crossref PubMed Scopus (75) Google Scholar APOL1 protein then creates cation selective channels in membranes, leading to depolarization, a continuous influx of sodium and calcium, followed by chloride and subsequent osmotic swelling of the cell and internal organelles (Figure 13Uzureau S. Lecordier L. Uzureau P. et al.APOL1 C-terminal variants may trigger kidney disease through interference with APOL3 control of actomyosin.Cell Rep. 2020; 30: 3821-3836.e3813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 4Hong X. Rosenberg A.Z. Zhang B. et al.Joint associations of maternal-fetal APOL1 genotypes and maternal country of origin with preeclampsia risk.Am J Kidney Dis. 2020; 5: 278-288Google Scholar, 5Sampson M.G. Robertson C.C. Martini S. et al.Integrative genomics identifies novel associations with APOL1 risk genotypes in Black NEPTUNE subjects.J Am Soc Nephrol. 2016; 27: 814-823Crossref PubMed Scopus (79) Google Scholar, 6Skorecki K.L. Lee J.H. Langefeld C.D. et al.A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy.Nephrol Dial Transplant. 2018; 33: 323-330Crossref PubMed Scopus (16) Google Scholar, 7Ryu J.H. Ge M. Merscher S. et al.APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice.PLoS One. 2019; 14e0211559Crossref PubMed Scopus (18) Google Scholar, 8Okamoto K. Rausch J.W. Wakashin H. et al.APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R.Commun Biol. 2018; 1: 188Crossref PubMed Scopus (31) Google Scholar, 9Zhang J.Y. Wang M. Tian L. et al.UBD modifies APOL1-induced kidney disease risk.Proc Natl Acad Sci U S A. 2018; 115: 3446-3451Crossref PubMed Scopus (32) Google Scholar, 10Giovinazzo J.A. Thomson R.P. Khalizova N. et al.Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity.Elife. 2020; 9e51185Crossref PubMed Scopus (24) Google Scholar, 11Dummer P.D. Limou S. Rosenberg A.Z. et al.APOL1 kidney disease risk variants: an evolving landscape.Semin Nephrol. 2015; 35: 222-236Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 12Lan X. Jhaveri A. Cheng K. et al.APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability.Am J Physiol Renal Physiol. 2014; 307: F326-F336Crossref PubMed Scopus (130) Google Scholar, 13Beckerman P. Bi-Karchin J. Park A.S. et al.Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.Nat Med. 2017; 23: 429-438Crossref PubMed Scopus (194) Google Scholar, 14Davis S.E. Khatua A.K. Popik W. Nucleosomal dsDNA stimulates APOL1 expression in human cultured podocytes by activating the cGAS/IFI16-STING signaling pathway.Sci Rep. 2019; 9: 15485Crossref PubMed Scopus (11) Google Scholar, 15Wakashin H. Heymann J. Roshanravan H. et al.APOL1 renal risk variants exacerbate podocyte injury by increasing inflammatory stress.BMC Nephrol. 2020; 21: 371Crossref PubMed Scopus (12) Google Scholar, 16Datta S. Kataria R. Zhang J.Y. et al.Kidney disease-associated APOL1 variants have dose-dependent, dominant toxic gain-of-function.J Am Soc Nephrol. 2020; 31: 2083-2096Crossref PubMed Scopus (19) Google Scholar, 17Chun J. Zhang J.Y. Wilkins M.S. et al.Recruitment of APOL1 kidney disease risk variants to lipid droplets attenuates cell toxicity.Proc Natl Acad Sci U S A. 2019; 116: 3712-3721Crossref PubMed Scopus (36) Google Scholar, 18Olabisi O.A. Heneghan J.F. APOL1 nephrotoxicity: what does ion transport have to do with it?.Semin Nephrol. 2017; 37: 546-551Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 19Granado D. Muller D. Krausel V. et al.Intracellular APOL1 risk variants cause cytotoxicity accompanied by energy depletion.J Am Soc Nephrol. 2017; 28: 3227-3238Crossref PubMed Scopus (52) Google Scholar, 20Shah S.S. Lannon H. Dias L. et al.APOL1 kidney risk variants induce cell death via mitochondrial translocation and opening of the mitochondrial permeability transition pore.J Am Soc Nephrol. 2019; 30: 2355-2368Crossref PubMed Scopus (39) Google Scholar, 21Ma L. Chou J.W. Snipes J.A. et al.APOL1 renal-risk variants induce mitochondrial dysfunction.J Am Soc Nephrol. 2017; 28: 1093-1105Crossref PubMed Scopus (78) Google Scholar, 22Nichols B. Jog P. Lee J.H. et al.Innate immunity pathways regulate the nephropathy gene apolipoprotein L1.Kidney Int. 2015; 87: 332-342Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 23Hayek S.S. Koh K.H. Grams M.E. et al.A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease.Nat Med. 2017; 23: 945-953Crossref PubMed Scopus (128) Google Scholar). These effects of APOL1 are inhibited in human-infective T.b. rhodesiense24Perez-Morga D. Vanhollebeke B. Paturiaux-Hanocq F. et al.Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes.Science. 2005; 309: 469-472Crossref PubMed Scopus (240) Google Scholar and T.b. gambiense,3Uzureau S. Lecordier L. Uzureau P. et al.APOL1 C-terminal variants may trigger kidney disease through interference with APOL3 control of actomyosin.Cell Rep. 2020; 30: 3821-3836.e3813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar,25Cooper A. Capewell P. Clucas C. et al.A primate APOL1 variant that kills Trypanosoma brucei gambiense.PLoS Negl Trop Dis. 2016; 10e0004903Crossref PubMed Scopus (16) Google Scholar each through a different resistance mechanism. This leads susceptible individuals to experience sleeping sickness, an acute infective form more common in East Africa caused by T.b. rhodesiense, or an indolent form more common in West Africa caused by T.b. gambiense. In turn, APOL1 G1 and G2 risk variants (RVs) modify susceptibility to African sleeping sickness. The G2 allele, even in the heterozygous state, confers protection from infection by T.b. rhodesiense, whereas G1 reduces severity of illness due to T.b. gambiense. However, homozygosity and compound heterozygosity (high-risk [HR] genotypes) increase susceptibility to nephropathy. The recent H3Africa study showed that the highest G1 frequencies were in West Africa, such as in the Côte d’Ivoire (43%) and the Fon population in Benin (34%).26Choudhury A. Aron S. Botigue L.R. et al.High-depth African genomes inform human migration and health.Nature. 2020; 586: 741-748Crossref PubMed Scopus (70) Google Scholar This is consistent with geographic correlation between the prevalence of APOL1 RVs and different forms of sleeping sickness. Interestingly, the frequency of G1 was markedly different between the Bantu versus Nilo-Sharan speaking Ugandans (14% vs. 2%), in contrast to similar frequencies of G2 in these groups.26Choudhury A. Aron S. Botigue L.R. et al.High-depth African genomes inform human migration and health.Nature. 2020; 586: 741-748Crossref PubMed Scopus (70) Google Scholar In summary, the only currently known biological function of APOL1 is conferring protection against trypanosomiasis. To increase protection from a potentially deadly disease, the allele frequency RV APOL1 rapidly increased in Africa.27Ko W.Y. Rajan P. Gomez F. et al.Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations.Am J Hum Genet. 2013; 93: 54-66Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar However, the newly evolved APOL1 RVs in homozygous form are associated with an increased long-term risk of kidney disease. Future studies should examine the role of the full spectrum of observed coding variants in APOL1 and their role in trypanosomiasis and kidney disease. Familial aggregation of end-stage kidney disease in African American families suggested an inherited basis for progressive nephropathy nearly 30 years ago.28Freedman B.I. Renal microvascular susceptibility in African American pedigrees.Transplant Proc. 1993; 25: 2423-2425PubMed Google Scholar, 29Freedman B.I. Spray B.J. Tuttle A.B. et al.The familial risk of end-stage renal disease in African Americans.Am J Kidney Dis. 1993; 21: 387-393Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 30Freedman B.I. Iskandar S.S. Appel R.G. The link between hypertension and nephrosclerosis.Am J Kidney Dis. 1995; 25: 207-221Abstract Full Text PDF PubMed Scopus (191) Google Scholar This concept was validated with the discovery of APOL1 association with a spectrum of nondiabetic forms of glomerulosclerosis in individuals with recent African ancestry,31Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1340) Google Scholar,32Tzur S. Rosset S. Shemer R. 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 (443) Google Scholar including focal segmental glomerulosclerosis or FSGS (all varieties), collapsing glomerulopathy (collapsing FSGS), and the syndrome of solidified or diffuse glomerulosclerosis with low-level proteinuria (often arterionephrosclerosis or hypertensive nephropathy).33Freedman B.I. Kopp J.B. Langefeld C.D. et al.The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans.J Am Soc Nephrol. 2010; 21: 1422-1426Crossref PubMed Scopus (197) Google Scholar, 34Nicholas Cossey L. Larsen C.P. Liapis H. Collapsing glomerulopathy: a 30-year perspective and single, large center experience.Clin Kidney J. 2017; 10: 443-449Crossref PubMed Scopus (23) Google Scholar, 35Freedman B.I. Cohen A.H. Hypertension-attributed nephropathy: what's in a name?.Nat Rev Nephrol. 2016; 12: 27-36Crossref PubMed Scopus (47) Google Scholar As shown in Table 1, kidney disease associated with sickle cell disease, systemic lupus erythematosus, and allograft failure in kidneys transplanted from donors with APOL1 HR genotypes also reside in the APOL1-associated nephropathy spectrum.36Larsen C.P. Beggs M.L. Saeed M. et al.Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy.J Am Soc Nephrol. 2013; 24: 722-725Crossref PubMed Scopus (136) Google Scholar, 37Ashley-Koch A.E. Okocha E.C. Garrett M.E. et al.MYH9 and APOL1 are both associated with sickle cell disease nephropathy.Br J Haematol. 2011; 155: 386-394Crossref PubMed Scopus (104) Google Scholar, 38Freedman B.I. Langefeld C.D. Andringa K.K. et al.End-stage renal disease in African Americans with lupus nephritis is associated with APOL1.Arthritis Rheumatol. 2014; 66: 390-396Crossref PubMed Scopus (183) Google Scholar, 39Freedman B.I. Locke J.E. Reeves-Daniel A.M. et al.Apolipoprotein L1 gene effects on kidney transplantation.Semin Nephrol. 2017; 37: 530-537Abstract Full Text Full Text PDF PubMed Scopus (18) Google ScholarTable 1APOL1-associated disease spectrumDiagnosisManifestations, risk conditions, and diagnosisAPOL1 associationOdds ratioPrimary FSGSNephrotic proteinuria, low serum albuminYes17Postadaptive FSGSRisk: Low birth weight, prematurity, increased body sizeFeature: normal serum albuminYesNDAPOL1 FSGSMay mimic other formsYesSee otherVirus-associated FSGSHIV-1, cytomegalovirus, Epstein-Barr virus, SARS-CoV-2, othersYes: HIV-129 (United States), 89 (South Africa)Drug-associated FSGSMany medicationsInterferonNDHypertension-attributed ESKD or presumed arterionephrosclerosisHypertension, subnephrotic proteinuria, and progressive loss of eGFRYes7Sickle cell nephropathyProteinuria, progressive renal diseaseYes2.7–5.4PreeclampsiaHypertension, proteinuriaYes1.8, 1.9eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; ND, not determined; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Open table in a new tab eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; ND, not determined; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. One end of the disease spectrum, which shows the strongest association with APOL1 RV, is collapsing glomerulopathy. It is seen with extremely high interferon levels, including interferon administration, HIV infection (HIV-associated nephropathy), systemic lupus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]–associated nephropathy).40Wu H. Larsen C.P. Hernandez-Arroyo C.F. et al.AKI and collapsing glomerulopathy associated with COVID-19 and APOL 1 high-risk genotype.J Am Soc Nephrol. 2020; 31: 1688-1695Crossref PubMed Scopus (124) Google Scholar,41Velez J.C.Q. Caza T. Larsen C.P. COVAN is the new HIVAN: the re-emergence of collapsing glomerulopathy with COVID-19.Nat Rev Nephrol. 2020; 16: 565-567Crossref PubMed Scopus (64) Google Scholar This fits the concept that interferon drives APOL1 transcription, resulting in abundant APOL1 RV protein in kidney cells. It is possible that massive immune system activation related to SARS-CoV-2 may occasionally cause nephropathy in individuals with G1G0 genotype, as reported with HIV-associated nephropathy on the African continent and a recipient of a G1G0 deceased donor kidney.42Kasembeli A.N. Duarte R. Ramsay M. et al.APOL1 risk variants are strongly associated with HIV-associated nephropathy in Black South Africans.J Am Soc Nephrol. 2015; 26: 2882-2890Crossref PubMed Scopus (195) Google Scholar Although kidney disease is the major manifestation of RV APOL1, it may also be associated with other phenotypes, such as sepsis and preeclampsia.43Reidy K.J. Hjorten R.C. Simpson C.L. et al.Fetal-not maternal-APOL1 genotype associated with risk for preeclampsia in those with African ancestry.Am J Hum Genet. 2018; 103: 367-376Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,44Bajaj A. Ihegword A. Qiu C. et al.Phenome-wide association analysis suggests the APOL1 linked disease spectrum primarily drives kidney-specific pathways.Kidney Int. 2020; 97: 1032-1041Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar In 3 independent studies, the HR genotype was associated with increased odds of preeclampsia in African Americans (odds ratio, 1.4–3.3), 2 under a recessive model and 1 under a dominant model.4Hong X. Rosenberg A.Z. Zhang B. et al.Joint associations of maternal-fetal APOL1 genotypes and maternal country of origin with preeclampsia risk.Am J Kidney Dis. 2020; 5: 278-288Google Scholar,43Reidy K.J. Hjorten R.C. Simpson C.L. et al.Fetal-not maternal-APOL1 genotype associated with risk for preeclampsia in those with African ancestry.Am J Hum Genet. 2018; 103: 367-376Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,45Miller A.K. Azhibekov T. O'Toole J.F. et al.Association of preeclampsia with infant APOL1 genotype in African Americans.BMC Med Genet. 2020; 21: 110Crossref PubMed Scopus (8) Google Scholar In each study, risk was conferred by the genotype of the fetus. The mother’s country of origin (United States vs. Haiti) and discordance between maternal and fetal APOL1 genotype seemed to modify the association. In 2 independent studies of Black patients with nephrotic syndrome, an HR APOL1 genotype was associated with increased odds of having been born preterm (odds ratio, 2.7–9.6).5Sampson M.G. Robertson C.C. Martini S. et al.Integrative genomics identifies novel associations with APOL1 risk genotypes in Black NEPTUNE subjects.J Am Soc Nephrol. 2016; 27: 814-823Crossref PubMed Scopus (79) Google Scholar,46Ng D.K. Robertson C.C. Woroniecki R.P. et al.APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.Nephrol Dial Transplant. 2017; 32: 983-990PubMed Google Scholar Finally, ∼50% of Black children with nephrotic syndrome or proteinuric kidney disease in the Nephrotic Syndrome Study Network and Chronic Kidney Disease in Children had an APOL1 HR genotype, and these children had a significantly lower estimated glomerular filtration rate at presentation and more rapid decline of estimated glomerular filtration rate.46Ng D.K. Robertson C.C. Woroniecki R.P. et al.APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.Nephrol Dial Transplant. 2017; 32: 983-990PubMed Google Scholar The phenotypic heterogeneity associated with APOL1 HR genotypes is poorly understood, and future studies shall focus on deeper mechanistic understanding. Risk conferred by APOL1 in nonrenal diseases appears much smaller than for collapsing FSGS, and a role for APOL1 RVs in cardiovascular disease and hypertension independent of kidney disease has not yet been established.44Bajaj A. Ihegword A. Qiu C. et al.Phenome-wide association analysis suggests the APOL1 linked disease spectrum primarily drives kidney-specific pathways.Kidney Int. 2020; 97: 1032-1041Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,47Grams M.E. Surapaneni A. Ballew S.H. et al.APOL1 kidney risk variants and cardiovascular disease: an individual participant data meta-analysis.J Am Soc Nephrol. 2019; 30: 2027-2036Crossref PubMed Scopus (14) Google Scholar,48Bick A.G. Akwo E. Robinson-Cohen C. et al.Association of APOL1 risk alleles with cardiovascular disease in Blacks in the Million Veteran Program.Circulation. 2019; 140: 1031-1040Crossref PubMed Scopus (20) Google Scholar APOL1-associated nephropathy is an autosomal recessive disorder with incomplete penetrance. Although 1 APOL1 RV is sufficient to protect from trypanosomiasis, increased disease risk is predominantly observed in people carrying 2 RVs. APOL1-induced trypanosome killing has been studied for decades. However, APOL1-induced toxicity in mammalian cells remains poorly understood. Drs. Pollak, Olabisi, Scales, Raper, and Susztak addressed aspects of cell injury3Uzureau S. Lecordier L. Uzureau P. et al.APOL1 C-terminal variants may trigger kidney disease through interference with APOL3 control of actomyosin.Cell Rep. 2020; 30: 3821-3836.e3813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar,5Sampson M.G. Robertson C.C. Martini S. et al.Integrative genomics identifies novel associations with APOL1 risk genotypes in Black NEPTUNE subjects.J Am Soc Nephrol. 2016; 27: 814-823Crossref PubMed Scopus (79) Google Scholar,6Skorecki K.L. Lee J.H. Langefeld C.D. et al.A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy.Nephrol Dial Transplant. 2018; 33: 323-330Crossref PubMed Scopus (16) Google Scholar and molecular mechanisms7Ryu J.H. Ge M. Merscher S. et al.APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice.PLoS One. 2019; 14e0211559Crossref PubMed Scopus (18) Google Scholar,8Okamoto K. Rausch J.W. Wakashin H. et al.APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R.Commun Biol. 2018; 1: 188Crossref PubMed Scopus (31) Google Scholar using cell culture and animal models9Zhang J.Y. Wang M. Tian L. et al.UBD modifies APOL1-induced kidney disease risk.Proc Natl Acad Sci U S A. 2018; 115: 3446-3451Crossref PubMed Scopus (32) Google Scholar (Figure 2). Scales emphasized the critical role of APOL1 haplotypes for G1- and G2-mediated cytotoxicity in cultured podocytes stably expressing APOL1 RVs.49Gupta N. Wang X. Wen X. et al.Domain-specific antibodies reveal differences in the membrane topologies of apolipoprotein L1 in serum and podocytes.J Am Soc Nephrol. 2020; 31: 2065-2082Crossref PubMed Scopus (13) Google Scholar,50Scales S.J. Gupta N. De Maziere A.M. et al.Apolipoprotein L1-specific antibodies detect endogenous APOL1 inside the endoplasmic reticulum and on the plasma membrane of podocytes.J Am Soc Nephrol. 2020; 31: 2044-2064Crossref PubMed Scopus (23) Google Scholar Specifically, the podocytotoxicity was dependent on the African APOL1 haplotype (E150/I228/K255), not simply the specific RV, even though there were no differences in localization or expression level between haplotypes.51Lannon H. Shah S.S. Dias L. et al.Apolipoprotein L1 (APOL1) risk variant toxicity depends on the haplotype background.Kidney Int. 2019; 96: 1303-1307Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar She demonstrated that critical thresholds of expression at the plasma membrane must be surpassed to achieve cytotoxicity. African G1/G2 APOL1 exits the endoplasmic reticulum and reaches the cell surface to cause toxicity (in agreement with Giovinazzo et al.10Giovinazzo J.A. Thomson R.P. Khalizova N. et al.Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity.Elife. 2020; 9e51185Crossref PubMed Scopus (24) Google Scholar), as indicated by the rescue effect of the endoplasmic reticulum–Golgi transport inhibitor brefeldin A. In addition, N-terminal splice variants of APOL1 lacking a fully functional signal sequence (isoforms B3 and C), which localize to the cytoplasmic face of the endoplasmic reticulum more than plasma membranes,11Dummer P.D. Limou S. Rosenberg A.Z. et al.APOL1 kidney disease risk variants: an evolving landscape.Semin Nephrol. 2015; 35: 222-236Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,49Gupta N. Wang X. Wen X. et al.Domain-specific antibodies reveal differences in the membrane topologies of apolipoprotein L1 in serum and podocytes.J Am Soc Nephrol. 2020; 31: 2065-2082Crossref PubMed Scopus (13) Google Scholar,50Scales S.J. Gupta N. De Maziere A.M. et al.Apolipoprotein L1-specific antibodies detect endogenous APOL1 inside the endoplasmic reticulum and on the plasma membrane of podocytes.J Am Soc Nephrol. 2020; 31: 2044-2064Crossref PubMed Scopus (23) Google Scholar were nontoxic.12Lan X. Jhaveri A. Cheng K. et al.APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability.Am J Physiol Renal Physiol. 2014; 307: F326-F336Crossref PubMed Scopus (130) Google Scholar She emphasized that future publications should report the full sequence of the APOL1 variants used for in vitro and in vivo studies. In a talk entitled “Re-Envisioning the APOL1 Cation Channel,” Raper showed interesting results produced by studying the channel function of APOL1 reconstituted in an in vitro bilayer system.10Giovinazzo J.A. Thomson R.P. Khalizova N. et al.Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity.Elife. 2020; 9e51185Crossref PubMed Scopus (24) Google Scholar,25Cooper A. Capewell P. Clucas C. et al.A primate APOL1 variant that kills Trypanosoma brucei gambiense.PLoS Negl Trop Dis. 2016; 10e0004903Crossref PubMed Scopus (16) Google Scholar Her team showed a population of active channels at the plasma membrane, resulting in an influx of Na+ and Ca2+ ions in human cells expressing APOL1 RVs. Interestingly, wild-type G0 and RV APOL1 did not differ in ion-conducting properties but manifested differences in pH gating and membrane insertion.10Giovinazzo J.A. Thomson R.P. Khalizova N. et al.Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity.Elife. 2020; 9e51185Crossref PubMed Scopus (24) Google Scholar All variants of APOL1 traffic to the plasma membrane; en route, they encounter acidification and neutralization along the secretory pathway, steps required for channel formation. However, although G1 and G2 are able to form cation channels when overexpressed, G0 does not. They hypothesize that G1 and G2 are activated at higher pH than G0, leading to channel formation (Figure 1). She suggested a model wherein APOL1-influenced channel activity is the upstream event causing cell death. Of particular importance, she also emphasized a potential public health issue because of the rapid evolution of Trypanosomal species in Africa in considering therapies that may only partially inhibit APOL1. These could lead to emergence of resistance mechanisms in parasites. Susztak emphasized that conditional and inducible expression of G1 or G2 variants in mouse podocytes52Kopp J.B. Anders H.J. Susztak K. et al.Podocytopathies. Nat Rev Dis Primers. 2020; 6: 68Crossref PubMed Scopus (87) Google Scholar induced proteinuria, foot process effacement, global glomerulosclerosis, and tubulointerstitial fibrosis, changes observed in patients with APOL1 HR genotypes.13Beckerman P. Bi-Karchin J. Park A.S. et al.Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.Nat Med. 2017; 23: 429-438Crossref PubMed Scopus (194) Google Scholar,53Beckerman P. Susztak K. APOL1: the balance imposed by infection, selection, and kidney disease.Trends Mol Med. 2018; 24: 682-695Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar These studies firmly established that APOL1 RVs are disease causative. Furthermore, gene expression analysis by RNA sequencing of tissue from mouse models with podocyte-specific RV expression showed striking similarities to those in patients with APOL1-associated FSGS. Disease severity in mice correlated with APOL1 genotype and total APOL1 expression. Her team observed differences in intracellular trafficking of APOL1, including a defect in acidification of endocytic vesicles, causing a defect in autophagy and downstream activation of the inflammasome.12Lan X. Jhaveri A. Cheng K. et al.APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability.Am J Physiol Renal Physiol. 2014; 307: F326-F336Crossref PubMed Scopus (130) Google Scholar,14Davis S.E. Khatua A.K. Popik W. Nucleosomal dsDNA stimulates APOL1 expression in human cultured podocytes by activating the cGAS/IFI16-STING signaling pathway.Sci Rep. 2019; 9: 15485Crossref PubMed Scopus (11) Google Scholar,15Wakashin H. Heymann J. Roshanravan H. et al.APOL1 renal risk variants exacerbate podocyte injury by increasing inflammatory stress.BMC Nephrol. 2020; 21: 371Crossref PubMed Scopus (12) Google Scholar Pollak noted that the G1 and G2 alleles are associated with different phenotypes in mice and humans, whereas G0 is generally less toxic in most but not all experimental systems.16Datta S. Kataria R. Zhang J.Y. et al.Kidney disease-associated APOL1 variants have dose-dependent, dominant toxic gain-of-function.J Am Soc Nephrol. 2020; 31: 2083-2096Crossref PubMed Scopus (19) Google Scholar Higher APOL1 RV expression levels associate with increasing toxicity in humans and experimental models. In most cases, 2 RVs are required for toxici" @default.
• W3152090481 created "2021-04-13" @default.
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• W3152090481 date "2021-06-01" @default.
• W3152090481 modified "2023-10-13" @default.
• W3152090481 title "APOL1 at 10 years: progress and next steps" @default.
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