Localization of APOL1 Protein and mRNA in the Human Kidney

Ma, Lijun; Shelness, Gregory S.; Snipes, James A.; Murea, Mariana; Antinozzi, Peter A.; Cheng, Dongmei; Saleem, Moin A.; Satchell, Simon C.; Banas, Bernhard; Mathieson, Peter W.; Kretzler, Matthias; Hemal, Ashok K.; Rudel, Lawrence L.; Petrovic, Snezana; Weckerle, Allison; Pollak, Martin R.; Ross, Michael D.; Parks, John S.; Freedman, Barry I.

doi:10.1681/asn.2013091017

Cited by 117 publications

(126 citation statements)

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“…APOL1 is predominantly present in the circulation and to a lesser extent in the liver and other solid organs, including the kidneys. Kidney APOL1 protein is enriched in glomerular podocytes, relative to proximal tubule and endothelial cells ( 5 ). Due to the abundance of APOL1 in human serum and uptake of free APOL1 into podocytes in vitro ( 5 ), it was initially hypothesized that circulating APOL1 protein might contribute to APOL1 -associated nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…An N-terminal APOL1 (1-199 amino acids)-MBP fusion protein was obtained, as previously reported ( 5,15 ). cDNA corresponding to APOL1 (amino acid residues 13-130 of the APOL1 reference sequence) was generated by PCR and cloned into the 3 ) were pooled and separated by nondenaturing gradient gel electrophoresis to determine the elution position of APOL1.…”

Section: Co-immunoprecipitationmentioning

confidence: 99%

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Characterization of circulating APOL1 protein complexes in African Americans

Weckerle

Snipes

Cheng

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org G1 and G2 renal-risk variants on chromosome 22q13.1 ( 1-3 ). Although APOL1 mRNA and APOL1 protein are present in human kidney ( 4, 5 ), the major APOL1 reservoir appears to be circulating protein ( 5, 6 ). APOL1 was initially discovered as a minor apolipoprotein of plasma HDLs ( 6 ); however, its distribution among HDL subfractions has not been well-defi ned. APOL1 nephropathy variants associate with HDL subfraction concentrations ( 7 ) and CVD risk, although controversial results have been reported with CVD ( 8-11 ). Trypanosome lytic factors (TLF1 and TLF2) contain APOL1 protein ( 12 ) and are minor HDL subfractions in humans that contribute to innate immunity via protection from infection, including from African trypanosomes ( 13 ).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 ). 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 ), it remains critical to determine whether serum APOL1 concentrations or the structure/composition of variant APOL1 proteins and their associated complexes are specifi c to the G1 and G2 renalrisk 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 immunoblot analysis. Proteomics analysis was performed to compare the composition of APOL1 protein-containing complexes. These 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. A major breakthrough in human molecular genetics was identifi cation of the powerful contribution of APOL1 gene ...

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Section: Discussionmentioning

confidence: 99%

Section: Co-immunoprecipitationmentioning

confidence: 99%

Characterization of circulating APOL1 protein complexes in African Americans

Weckerle

Snipes

Cheng

et al. 2016

Journal of Lipid Research

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“…Because of the elevated risks for cardiovascular disease (CVD) and heart failure (HF) among people with chronic kidney disease compared with the general population,15 investigation of the cardiovascular risk of individuals who carry the APOL1 high‐risk variants is an issue of active study. Apolipoprotein L1 (Apol1) has been localized to endothelial and vascular smooth muscle cells within the kidney16, 17 and is also known to circulate in plasma with high‐density lipoprotein particles,18, 19 suggesting a potential role of the APOL1 risk variants in CVD. Studies to date on this topic, however, have been conflicting.…”

Section: Introductionmentioning

confidence: 99%

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

Chen

Katz

Estrella

et al. 2017

JAHA

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Background APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self‐identified black participants of MESA (Multi‐Ethnic Study of Atherosclerosis).Methods and ResultsCross‐sectional associations of APOL1 genotypes (high‐risk=2 alleles; low‐risk=0 or 1 allele) with coronary artery calcification, carotid‐intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C–based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high‐risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid‐intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high‐risk group was 82% more likely to develop incident heart failure compared with the low‐risk group (95% confidence interval, 1.01–3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00–3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03–3.35) slightly attenuated this association. The APOL1 high‐risk genotypes were not significantly associated with other clinical CVD outcomes.ConclusionsAmong blacks without baseline CVD, the APOL1 high‐risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD.

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“…APOL1 is expressed in medium-sized arterial and arteriolar endothelial cells in normal and diseased kidney sections (8). Ma et al identified APOL1 mRNA and protein expression in glomerular and interstitial endothelial cells (24). Consistent with these in vitro findings, a recent publication demonstrated that individuals with two APOL1 risk alleles exhibit a 2-fold increased risk of cardiovascular disease events compared with individuals with no risk alleles, irrespective of the presence of clinical kidney disease (25).…”

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confidence: 76%