APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors

Freedman, Barry I.; Pastan, Stephen O.; Israni, Ajay K.; Schladt, David; Julian, Bruce A.; Gautreaux, Michael D.; Hauptfeld, Věra; Bray, Robert A.; Gebel, Howard M.; Kirk, Allan D.; Gaston, Robert S.; Rogers, Jeffrey; Farney, Alan C.; Orlando, Giuseppe; Stratta, Robert J.; Mohan, Sumit; Ma, Lijun; Langefeld, Carl D.; Bowden, Donald W.; Hicks, Pamela J.; Palmer, Nicholette D.; Palanisamy, A.; Reeves‐Daniel, Amber; Brown, W. Mark; Divers, Jasmin

doi:10.1097/tp.0000000000000969

Cited by 146 publications

(142 citation statements)

References 29 publications

(51 reference statements)

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“…APOL1 in the tubules could partly be imported from the circulation or urine. However, circulating levels of APOL1 do not associate with categorical or quantitative CKD phenotypes (15,16), and others have shown that poor kidney allograft outcomes are associated with the APOL1 genotype of the transplanted kidney and not the recipient (17,22). Together, these results suggest that APOL1 synthesized in the podocyte mediates the pathogenesis of APOL1-associated kidney diseases.…”

Section: Discussionsupporting

confidence: 49%

APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

Madhavan¹,

O’Toole²,

Konieczkowski³

et al. 2017

JCI Insight

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Section: Discussionsupporting

confidence: 49%

APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

Madhavan¹,

O’Toole²,

Konieczkowski³

et al. 2017

JCI Insight

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“…Three studies demonstrate that risk to the kidney allograft travels with the donor kidney genotype (2, 29–31). Another study found that recipient APOL1 genotype had no effect on survival of kidney allografts (32).…”

Section: Is Circulating Apol1 or Apol1 Of Kidney Origin The Disease-cmentioning

confidence: 99%

Apolipoprotein L1 and Kidney Disease in African Americans

Friedman

Pollak

2016

Trends in Endocrinology & Metabolism

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Genetic variants in the Apolipoprotein L1 (APOL1) gene cause high rates of kidney disease in African Americans. These variants, found only in individuals with recent African ancestry, confer enhanced innate immunity against African trypanosomes. Though they are among the most powerful disease-causing common variants discovered to date, we are just beginning to understand how they promote kidney injury. Since APOL1 is only present in a few primate species, much of our current knowledge has come from natural experiments in humans and in vitro studies while awaiting the development of transgenic animal models. Understanding more about the function of ApoL1 and how the high-risk variants behave differently from other ApoL1 molecules is a high priority in kidney disease research.

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“…19,20 In kidney transplantation, donor expression of APOL1 risk variants confers risk of graft failure. [21][22][23][24] Overexpression of APOL1 in cultured human kidney epithelial cells induces cytotoxic effects. [25][26][27] APOL1 is restricted to humans and some nonhuman primate species.…”

mentioning

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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APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors

Cited by 146 publications

References 29 publications

APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

Apolipoprotein L1 and Kidney Disease in African Americans

APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death

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