APOL1 Nephrotoxicity: What Does Ion Transport Have to Do With It?

Olabisi, Opeyemi; Heneghan, John F.

doi:10.1016/j.semnephrol.2017.07.008

Cited by 19 publications

(14 citation statements)

References 35 publications

(62 reference statements)

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“…The full‐length APOL1 wild‐type protein G0 has been subdivided into four domains: SP (1–27 AA), pore‐forming domain (PFD, 60–237 AA), membrane‐address domain (MAD, 238–303 AA), and serum resistance‐associated protein‐interacting domain (339–398) . We and others have reported that the PFD plays a critical role in APOL1 function .…”

Section: Introductionmentioning

confidence: 99%

“…However, in these models, comparative analysis of APOL1 risk and nonrisk proteins was not conducted. Nonetheless, the cellular expression of APOL1 risk variants has been shown to enhance K + efflux and activation of the mitogen‐activated protein kinase pathway in 293 T cells . Moreover, this effect of APOL1 risk alleles resulted in cytotoxicity, which was dose‐dependent .…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

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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“…APOL1 protein is known to form ion permeable pores in endosomal membranes of trypanosomes, allowing endosomal contents to leak into the cytoplasm and disrupt the molecular milieu [24]. Pore formation has also been reported to occur in HEK293 cells when APOL1 is over-expressed,[17] bolstering an emerging hypothesis that APOL1 -associated kidney damage may be due to toxic APOL1 -mediated pore formation [25]. However, previous investigations have yielded conflicting results with regard to risk-variant mediated disruption of ion concentrations.…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes

et al. 2019

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Kidney failure occurs in 5–13% of individuals with sickle cell disease and is associated with early mortality. Two APOL1 alleles (G1 and G2) have been identified as risk factors for sickle cell disease nephropathy. Both risk alleles are prevalent in individuals with recent African ancestry and have been associated with nephropathic complications in other diseases. Despite the association of G1 and G2 with kidney dysfunction, the mechanisms by which these variants contribute to increased risk remain poorly understood. Previous work in zebrafish models suggest that the G2 risk allele functions as a dominant negative, whereas the G1 allele is a functional null. To understand better the cellular pathology attributed to APOL1 G2, we investigated the in vivo effects of the G2 risk variant on distinct cell types using RNA sequencing. We surveyed APOL1 G2 associated transcriptomic alterations in podocytes and vascular endothelial cells isolated from zebrafish larvae expressing cell-type specific reporters. Our analysis identified many transcripts (n = 7,523) showing differential expression between APOL1 G0 (human wild-type) and APOL1 G2 exposed podocytes. Conversely, relatively few transcripts (n = 107) were differentially expressed when comparing APOL1 G0 and APOL1 G2 exposed endothelial cells. Pathway analysis of differentially expressed transcripts in podocytes showed enrichment for autophagy associated terms such as “Lysosome” and “Phagosome”, implicating these pathways in APOL1 G2 associated kidney dysfunction. This work provides insight into the molecular pathology of APOL1 G2 nephropathy which may offer new therapeutic strategies for multiple disease contexts such as sickle cell nephropathy.

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“…Indeed, studies by the Pollak group indicate the role of potassium efflux in mammalian cytotoxicity as well [76, 77]. Exogenous expression of APOL1 using APOL1 cRNA injections in Xenopus oocytes increased ion permeability and induced morphological toxicity [78].…”

Section: Apol1-mediated Trypanosome Lysis and Renal Injury: Similar Mmentioning

confidence: 99%

APOL1: The Balance Imposed by Infection, Selection, and Kidney Disease

Beckerman

Suszták

2018

Trends in Molecular Medicine

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Chronic kidney disease (CKD) affects millions of people and constitutes a major health and financial burden worldwide. People of African descent are at an increased risk of developing kidney disease, which is mostly explained by two variants in the Apolipoprotein L1 (APOL1) gene that are found only in people of west African origin. It is hypothesized that these variants were genetically selected due to the protection they afford against African sleeping sickness, caused by the parasite Trypanosoma brucei. Targeting mutant APOL1 could have substantial therapeutic potential for treating kidney disease. In this review, we will describe the intriguing interplay between microbiology, genetics, and kidney disease as revealed in APOL1-associated kidney disease, discuss APOL1-induced cytotoxicity and its therapeutic implications.

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APOL1 Nephrotoxicity: What Does Ion Transport Have to Do With It?

Cited by 19 publications

References 35 publications

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

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

RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes

APOL1: The Balance Imposed by Infection, Selection, and Kidney Disease

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