Mutations in APOL1 are associated with an increased risk of renal disease and are found at a high frequency in people of African ancestry. Two recent studies used transgenic Drosophila melanogaster models to investigate the molecular mechanisms that underlie APOL1-associated renal disease.
Karl Skorecki and colleagues showed that expression of APOL1-G1 or G2 risk variants in Drosophila nephrocytes — which are homologous to human podocytes — resulted in the accumulation of an endocytic tracer, followed by nephrocyte loss in older flies. Further investigations in Saccharomyces cerevisiae provided evidence that APOL1 risk alleles impair endosomal trafficking and vacuole acidification.
Similarly, Zhe Han and colleagues found that nephrocyte-specific expression of APOL1 or APOL1-G1 in Drosophila resulted in increased endocytic activity and reduced organelle acidification, followed by a loss of function, increase in size and premature death of nephrocytes as the flies aged. The phenotype was most severe in flies that expressed APOL1-G1 and was similar to that of cultured mammalian podocytes that overexpress this risk allele.
“APOL1 risk alleles impair endosomal trafficking and vacuole acidification”
“To observe fly renal cell dysfunction as a result of expressing APOL1 in nephrocytes, and to be able to relate the resulting phenotypes to APOL1-associated pathology of human podocytes, is a major advance for the use of Drosophila as a biomedical model with clinical relevance,” says Han. “The findings also tell us some very important things about APOL1 protein function. I am confident that genetic screening in Drosophila will unveil interaction networks of proteins and pathways with APOL1 that will significantly advance our understanding of the mechanisms by which APOL1 causes kidney disease.”
Fu, Y. et al. APOL1-G1 in nephrocytes induces hypertrophy and accelerates cell death. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2016050550 (2016)
Kruzel-Davila, E. et al. APOL1-mediated cell injury involves disruption of conserved trafficking processes. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2016050546 (2016)
About this article
Cite this article
Carney, E. Mechanisms of APOL1-associated renal disease. Nat Rev Nephrol 13, 62 (2017). https://doi.org/10.1038/nrneph.2016.175
ApoL1 renal risk variants induce aberrant THP-1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase-2
American Journal of Physiology-Renal Physiology (2018)
HLA-DQA1 and APOL1 as Risk Loci for Childhood-Onset Steroid-Sensitive and Steroid-Resistant Nephrotic Syndrome
American Journal of Kidney Diseases (2018)