Apolipoprotein L1 and Kidney Disease in African Americans

Friedman, David J.; Pollak, Martin R.

doi:10.1016/j.tem.2016.02.002

Cited by 75 publications

(67 citation statements)

References 82 publications

(138 reference statements)

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“…6) 31–34 . This rationale is supported by the fact that the APOL1 gene encodes a signal peptide sequence that targets newly synthesized protein for secretion, by the fact that exogenously added APOL1 risk-variant proteins, but not the non-risk-variant, affected endocytic machinery within podocytes (formation of autophagosomes)—the mechanism through which APOL1 risk proteins lyse trypanosomes 29 —and lastly, by studies describing suPAR–β 3 integrin-dependent endocytosis of hantaviruses 35,36 . Interestingly, a previous study showed that podocyte-specific expression of APOL1 risk variants in mice resulted in moderate podocyte depletion later in life and occasional preeclampsia 9 .…”

Section: Discussionmentioning

confidence: 99%

A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

Hayek

Koh

Grams

et al. 2017

Nat Med

180

170

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Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

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Section: Discussionmentioning

confidence: 99%

A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

Hayek

Koh

Grams

et al. 2017

Nat Med

180

170

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“…Initially, the role of circulating APOL1 was recognized as a trypanolytic factor . Until a decade ago, the role of the expressed protein in general, and in kidney cells in particular, was not appreciated . During the current decade, APOL1 mutants (G1 and G2) have been reported for their association with a higher incidence of chronic kidney disease in patients with African ancestry and considered to be renal risk variants (RRVs).…”

Section: Introductionmentioning

confidence: 99%

Alterations in plasma membrane ion channel structures stimulate NLRP3 inflammasome activation in APOL1 risk milieu

et al. 2019

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We evaluated alterations in the structural configurations of channels and activation of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome formation in apolipoprotein L1 (APOL1) risk and nonrisk milieus. APOL1G1-and APOL1G2-expressing podocytes (PD) displayed enhanced K + efflux, induction of pyroptosis, and escalated transcription of interleukin (IL)-1b and IL-18. APOL1G1-and APOL1G2-expressing PD promoted the transcription as well as translation of proteins involved in the formation of inflammasomes. Since glyburide (a specific inhibitor of K + efflux channels) inhibited the transcription of NLRP3, IL-1b, and IL-18, the role of K + efflux in the activation of inflammasomes in APOL1 risk milieu was implicated. To evaluate the role of structural alterations in K + channels in plasma membranes, bioinformatics studies, including molecular dynamic simulation, were carried out. Superimposition of bioinformatics reconstructions of APOL1G0, G1, and G2 showed several aligned regions. The analysis of pore-lining residues revealed that Ser342 and Tyr389 are involved in APOL1G0 pore formation and the altered conformations resulting from the Ser342Gly and Ile384Met mutation in the case of APOLG1 and deletion of the Tyr389 residue in the case of APOL1G2 are expected to alter pore characteristics, including K + ion selectivity. Analysis of multiple membrane (lipid bilayer) models of interaction with the peripheral protein, integral membrane protein, and multimer protein revealed that for an APOL1 multimer model, APOL1G0 is not energetically favorable while the APOL1G1 and APOL1G2 moieties favor the insertion of multiple ion channels into the lipid bilayer. We conclude that altered pore configurations carry the potential to facilitate K + ion transport in APOL1 risk milieu.Abbreviations AA, amino acid; APOL1, apolipoprotein L1; APOL1G0, APOL1 nonrisk allele; APOL1G1 and G2, APOL1 risk alleles/

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“…[1][2][3][4][5][6] APOL1 is the serum trypanosome lytic factor. 7 A high frequency of two APOL1 risk alleles associated with renal diseases in persons of African ancestry [8][9][10] is attributed to the evolution of trypanosome resistance to an ancestral G0 allele, whereas G1 and G2 variant riskassociated alleles confer pathogen resistance.…”

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confidence: 99%

APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death

Zhu

Richman

et al. 2016

JASN

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People of African ancestry carrying certain APOL1 mutant alleles are at elevated risk of developing renal diseases. However, the mechanisms underlying APOL1-associated renal diseases are unknown. Because the APOL1 gene is unique to humans and some primates, new animal models are needed to understand the function of APOL1 in vivo. We generated transgenic Drosophila fly lines expressing the human APOL1 wild type allele (G0) or the predominant APOL1 risk allele (G1) in different tissues. Ubiquitous expression of APOL1 G0 or G1 in Drosophila induced lethal phenotypes, and G1 was more toxic than was G0. Selective expression of the APOL1 G0 or G1 transgene in nephrocytes, fly cells homologous to mammalian podocytes, induced increased endocytic activity and accumulation of hemolymph proteins, dextran particles, and silver nitrate. As transgenic flies with either allele aged, nephrocyte function declined, cell size increased, and nephrocytes died prematurely. Compared with G0-expressing cells, however, G1-expressing cells showed more dramatic phenotypes, resembling those observed in cultured mammalian podocytes overexpressing APOL1-G1. Expressing the G0 or G1 APOL1 transgene in nephrocytes also impaired the acidification of organelles. We conclude that expression of an APOL1 transgene initially enhances nephrocyte function, causing hypertrophy and subsequent cell death. This new Drosophila model uncovers a novel mechanism by which upregulated expression of APOL1-G1 could precipitate renal disease in humans. Furthermore, this model may facilitate the identification of APOL1-interacting molecules that could serve as new drug targets to treat APOL1-associated renal diseases.

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Apolipoprotein L1 and Kidney Disease in African Americans

Cited by 75 publications

References 82 publications

A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

Alterations in plasma membrane ion channel structures stimulate NLRP3 inflammasome activation in APOL1 risk milieu

APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death

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