TY - JOUR
T1 - The evolving story of apolipoprotein L1 nephropathy
T2 - the end of the beginning
AU - Daneshpajouhnejad, Parnaz
AU - Kopp, Jeffrey B.
AU - Winkler, Cheryl A.
AU - Rosenberg, Avi Z.
N1 - Funding Information:
This work was supported by the Intramural Research Programs, NIDDK, NIH, Bethesda, MD, USA (ZO1 DK043308, to J.B.K.) and has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract 75N91019D00024 (to C.A.W.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. The authors also thank Al Kane, Scientific Publications, Graphics, and Media, Frederick National Laboratory for Cancer Research and Erina He, Visual Arts, NIH, for assistance with the figures before submission.
Funding Information:
This work was supported by the Intramural Research Programs, NIDDK, NIH, Bethesda, MD, USA (ZO1 DK043308, to J.B.K.) and has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract 75N91019D00024 (to C.A.W.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. The authors also thank Al Kane, Scientific Publications, Graphics, and Media, Frederick National Laboratory for Cancer Research and Erina He, Visual Arts, NIH, for assistance with the figures before submission.
Publisher Copyright:
© 2022, Springer Nature Limited.
PY - 2022/5
Y1 - 2022/5
N2 - Genetic coding variants in APOL1, which encodes apolipoprotein L1 (APOL1), were identified in 2010 and are relatively common among individuals of sub-Saharan African ancestry. Approximately 13% of African Americans carry two APOL1 risk alleles. These variants, termed G1 and G2, are a frequent cause of kidney disease — termed APOL1 nephropathy — that typically manifests as focal segmental glomerulosclerosis and the clinical syndrome of hypertension and arterionephrosclerosis. Cell culture studies suggest that APOL1 variants cause cell dysfunction through several processes, including alterations in cation channel activity, inflammasome activation, increased endoplasmic reticulum stress, activation of protein kinase R, mitochondrial dysfunction and disruption of APOL1 ubiquitinylation. Risk of APOL1 nephropathy is mostly confined to individuals with two APOL1 risk variants. However, only a minority of individuals with two APOL1 risk alleles develop kidney disease, suggesting the need for a ‘second hit’. The best recognized factor responsible for this ‘second hit’ is a chronic viral infection, particularly HIV-1, resulting in interferon-mediated activation of the APOL1 promoter, although most individuals with APOL1 nephropathy do not have an obvious cofactor. Current therapies for APOL1 nephropathies are not adequate to halt progression of chronic kidney disease, and new targeted molecular therapies are in clinical trials.
AB - Genetic coding variants in APOL1, which encodes apolipoprotein L1 (APOL1), were identified in 2010 and are relatively common among individuals of sub-Saharan African ancestry. Approximately 13% of African Americans carry two APOL1 risk alleles. These variants, termed G1 and G2, are a frequent cause of kidney disease — termed APOL1 nephropathy — that typically manifests as focal segmental glomerulosclerosis and the clinical syndrome of hypertension and arterionephrosclerosis. Cell culture studies suggest that APOL1 variants cause cell dysfunction through several processes, including alterations in cation channel activity, inflammasome activation, increased endoplasmic reticulum stress, activation of protein kinase R, mitochondrial dysfunction and disruption of APOL1 ubiquitinylation. Risk of APOL1 nephropathy is mostly confined to individuals with two APOL1 risk variants. However, only a minority of individuals with two APOL1 risk alleles develop kidney disease, suggesting the need for a ‘second hit’. The best recognized factor responsible for this ‘second hit’ is a chronic viral infection, particularly HIV-1, resulting in interferon-mediated activation of the APOL1 promoter, although most individuals with APOL1 nephropathy do not have an obvious cofactor. Current therapies for APOL1 nephropathies are not adequate to halt progression of chronic kidney disease, and new targeted molecular therapies are in clinical trials.
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U2 - 10.1038/s41581-022-00538-3
DO - 10.1038/s41581-022-00538-3
M3 - Review article
C2 - 35217848
AN - SCOPUS:85125195527
SN - 1759-507X
VL - 18
SP - 307
EP - 320
JO - Nature Clinical Practice Nephrology
JF - Nature Clinical Practice Nephrology
IS - 5
ER -