APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability

Lan, Xiqian; Jhaveri, Aakash; Cheng, Kang; Wen, Hongxiu; Saleem, Moin A.; Mathieson, Peter W.; Mikulak, Joanna; Aviram, Sharon; Malhotra, Ashwani; Skorecki, Karl; Singhal, Pravin C.

doi:10.1152/ajprenal.00647.2013

Cited by 155 publications

(217 citation statements)

References 48 publications

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“…Furthermore, expression of G0 (wild-type) APOL1 appears to induce programmed cell death, although the exact mechanism has yet to be determined. Prior reports on the main mechanism of APOL1-induced cell death implicate the autophagic pathway ( 19,22 ), while others have shown that APOL1 induces podocyte necrosis by compromising lysosomal membrane permeability ( 25 ). Major goals of the present study were to elucidate the pathway of APOL1-induced cell death, as well as general outcomes of APOL1 expression in liver whether autophagy was involved in the cytotoxicity of APOL1 and its disease variants in our inducible cell lines, we fi rst performed Western blot analysis to examine LC3-II accumulation, a reliable marker of autophagy.…”

Section: Discussionmentioning

confidence: 99%

Biogenesis and cytotoxicity of APOL1 renal risk variant proteins in hepatocytes and hepatoma cells

Cheng¹,

Weckerle²,

Yu³

et al. 2015

Journal of Lipid Research

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reduced levels of calcifi ed atherosclerotic plaque in coronary and carotid arteries ( 3,4 ).APOL1 nephropathy risk variants have undergone positive selection in sub-Saharan Africa due to protection from Trypanosoma brucei rhodesiense , a cause of African sleeping sickness ( 5 ). The mechanism whereby APOL1 risk variant (G1 and G2) proteins kill trypanosomes is well-understood, and refl ects APOL1 protein uptake by parasites, traffi cking to the lysosome, and an acidic pH-induced conformational change with subsequent APOL1 protein insertion into lysosomal membranes. Chloride transport ensues via the APOL1 channel with osmotic swelling and eventual lysosomal rupture leading to parasite death. In contrast, the mechanism(s) whereby APOL1 renal risk variants produce progressive nondiabetic nephropathy remain poorly understood. Moreover, the basic biology of APOL1 proteins has not yet been elucidated and will be of utmost importance to defi ne its role in human diseases. We and others have shown that APOL1 mRNA and protein are present in podocytes, renal tubule cells, and glomerular endothelial cells, but not in mesangial cells ( 6, 7 ). APOL1 protein is also present in the circulation ( 8 ) and may thus play an important role in its pathology.Although APOL1 is produced by several cell types ( 9, 10 ), few details regarding its production and secretion are known. APOL1 is reported to bind to HDL ( 8 ). Because the liver is a major source of HDL production ( 11 ) and circulating apolipoproteins, and is likely an important contributor to the circulating pool of APOL1, the present study was performed using a hepatoma cell line and primary hepatocytes. These studies have revealed novel traffi cking behavior of APOL1 and identify potential pathways involved in APOL1-induced cell injury and death.Abstract Two APOL1 gene variants, which likely evolved to protect individuals from African sleeping sickness, are strongly associated with nondiabetic kidney disease in individuals with recent African ancestry. Consistent with its role in trypanosome killing, the pro-death APOL1 protein is toxic to most cells, but its mechanism of cell death is poorly understood and little is known regarding its intracellular traffi cking and secretion. Because the liver appears to be the main source of circulating APOL1, we examined its secretory behavior and mechanism of toxicity in hepatoma cells and primary human hepatocytes. APOL1 is poorly secreted in vitro, even in the presence of chemical chaperones; however, it is effi ciently secreted in wild-type transgenic mice, suggesting that APOL1 secretion has specialized requirements that cultured cells fail to support. In hepatoma cells, inducible expression of APOL1 and its risk variants promoted cell death, with the G1 variant displaying the highest degree of toxicity. To explore the basis for APOL1-mediated cell toxicity, endoplasmic reticulum stress, pyroptosis, autophagy, and apoptosis were examined. Our results suggest that autophagy represents the predominant mechanism of APOL1-mediated ce...

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Section: Discussionmentioning

confidence: 99%

Biogenesis and cytotoxicity of APOL1 renal risk variant proteins in hepatocytes and hepatoma cells

Cheng¹,

Weckerle²,

Yu³

et al. 2015

Journal of Lipid Research

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“…Furthermore, a recent study describes the influence of APOL1 risk variants on enhanced podocyte necrosis through compromised lysosomal membrane permeability. 23 Much remains to be explored in this area, including, the full degree of heterogeneous individual glomerular enlargement that the estimate of average V glom disguises, 17,24 and indices of podocyte number and density in the younger and older at-risk subjects 25 in the various APOL1 subgroups. This series is not a resource for the study of kidney disease, because such subjects were deliberately excluded.…”

Section: The Similarity Of Thementioning

confidence: 99%

APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults

Hoy

Hughson

Kopp

et al. 2015

Journal of the American Society of Nephrology

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APOL1 genetic variants contribute to kidney disease in African Americans. We assessed correlations between APOL1 profiles and renal histological features in subjects without renal disease. Glomerular number (N glom ) and mean glomerular volume (V glom ) were measured by the dissector/fractionator method in kidneys of African-American and non-African-American adults without renal disease, undergoing autopsies in Jackson, Mississippi. APOL1 risk alleles were genotyped and the kidney findings were evaluated in the context of those profiles. The proportions of African Americans with none, one, and two APOL1 risk alleles were 38%, 43%, and 19%, respectively; 38% of African Americans had G1 allele variants and 31% of African Americans had G2 allele variants. Only APOL1-positive African Americans had significant reductions in N glom and increases in V glom with increasing age. Regression analysis predicted an annual average loss of 8834 (P=0.03, sex adjusted) glomeruli per single kidney over the first 38 years of adult life in African Americans with two risk alleles. Body mass index above the group medians, but below the obesity definition of $30 kg/m 2 , enhanced the expression of age-related changes in N glom in African Americans with either one or two APOL1 risk alleles. These findings indicate that APOL1 risk alleles are associated with exaggerated age-related nephron loss, probably decaying from a larger pool of smaller glomeruli in early adult life, along with enlargement of the remaining glomeruli. These phenomena might mark mechanisms of accentuated susceptibility to kidney disease in APOL1-positive African Americans.

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“…The evidence against a loss-of-function model (in which APOL1 is a protective factor in the kidney) include: (1) APOL1 does not appear to be required for normal kidney function because a human homozygous null individual has been identified with apparently normal kidney function after several years of follow-up, 8,9 (2) the restricted species distribution of the APOL1 gene, 10,11 and (3) evidence for increased cytotoxic effects of G1 and G2 APOL1 when expressed in a variety of model systems. 7,[12][13][14] The bulk of APOL1 is found in the plasma, where it circulates as part of a specialized HDL particle consisting of APOA1, APOL1 and the hemoglobin binding protein HaptoglobinRelated Protein (HPR), which also serves as the receptor for uptake by trypanosomes. 15 A subset of APOL1-HDL has also been shown to bind IgM and forms the distinct lytic factor TLF-2.…”

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confidence: 99%

Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort

Kozlitina

Zhou

Brown

et al. 2016

JASN

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Two common missense variants in APOL1 (G1 and G2) have been definitively linked to CKD in black Americans. However, not all individuals with the renal-risk genotype develop CKD, and little is known about how APOL1 variants drive disease. Given the association of APOL1 with HDL particles, which are cleared by the kidney, differences in the level or quality of mutant APOL1-HDL particles could be causal for disease and might serve as a useful risk stratification marker. We measured plasma levels of G0 (low risk), G1, and G2 APOL1 in 3450 individuals in the Dallas Heart Study using a liquid chromatography-MS method that enabled quantitation of the different variants. Additionally, we characterized native APOL1-HDL from donors with no or two APOL1 risk alleles by size-exclusion chromatography and analysis of immunopurified APOL1-HDL particles. Finally, we identified genetic loci associated with plasma APOL1 levels and tested for APOL1-dependent association with renal function. Although we replicated the previous association between APOL1 variant status and renal function in nondiabetic individuals, levels of circulating APOL1 did not associate with microalbuminuria or GFR. Furthermore, the size or known components of APOL1-HDL did not consistently differ in subjects with the renal-risk genotype. Genetic association studies implicated variants in loci harboring haptoglobin-related protein (HPR), APOL1, and ubiquitin D (UBD) in the regulation of plasma APOL1 levels, but these variants did not associate with renal function. Collectively, these data demonstrate that the risk of renal disease associated with APOL1 is probably not related to circulating levels of the mutant protein.

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APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability

Cited by 155 publications

References 48 publications

Biogenesis and cytotoxicity of APOL1 renal risk variant proteins in hepatocytes and hepatoma cells

Biogenesis and cytotoxicity of APOL1 renal risk variant proteins in hepatocytes and hepatoma cells

APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults

Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort

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