Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

Abstract

African-Americans have an increased risk of developing chronic and end-stage kidney disease, with much of it attributed to two common genetic variants in the APOL1 gene, termed G1 and G2. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking as the APOL1 gene is only present in some primates and humans; thus experimental proof of causality of these risk alleles for renal disease has been challenging. Here, we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not the G0 allele, develop functional (albuminuria, azotemia), structural (foot process effacement and glomerulosclerosis) and molecular (gene expression) changes that closely resemble the human kidney disease. Disease development was cell-type specific, and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the APOL1 risk alleles interferes with endosomal trafficking and blocks autophagic flux, leading ultimately to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first in vivo demonstration that expression of APOL1 risk alleles are causal for altered podocyte function and glomerular disease.

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

“…Together, these results suggest that the risk variants are more likely altering a functional role of APOL1, as opposed to its cellular distribution or subcellular localization. In contrast to these results, another study showed that variant APOL1s had increased localization with RAB7-and RAB11-labeled endosomes compared with G0 in transiently transfected HEK293 cells and cultured human podocytes (24).…”

“…Localization of VAMP8 with its cognate autophagosomal SNARE partner STX17 is diminished in presence of APOL1 variants (24). In addition, mice and Drosophila transgenic for human APOL1 kidney disease risk variants have been shown to have disordered endosomal trafficking and variant-dependent glomerular and nephrocyte injury (24,34,35). Our results suggest a model in which APOL1, in concert with VAMP8 or other SNARE proteins, identifies vesicles containing cargo capable of mediating cellular damage and their functional interaction mediates a cellular response capable of attenuating/mitigating the pathogenic potential of these cargos.…”

“…APOL1-dependent mechanisms of trypanolysis involve endolysosomal pathways (27,31,32), and VAMP8 mediates fusion between late endosomes and lysosomes (33). Localization of VAMP8 with its cognate autophagosomal SNARE partner STX17 is diminished in presence of APOL1 variants (24). In addition, mice and Drosophila transgenic for human APOL1 kidney disease risk variants have been shown to have disordered endosomal trafficking and variant-dependent glomerular and nephrocyte injury (24,34,35).…”

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

“…While significant advances have been made in our understanding of APOL1 ‐associated kidney disease,14 the specific mechanisms by which these genetic variants cause kidney disease remain uncertain. Because of the elevated risks for cardiovascular disease (CVD) and heart failure (HF) among people with chronic kidney disease compared with the general population,15 investigation of the cardiovascular risk of individuals who carry the APOL1 high‐risk variants is an issue of active study.…”

Animal Models of Fetal Medicine and Obstetrics

“…Transgenic mice models can be generated to study the influence of relevant genes. The APOL1 gene encodes apolipoprotein L1, and variants of the gene (APOL1-G1 and -G2) are associated with kidney disease [49]. As the gene is only found in humans and some primates, transgenic mice models were developed to study the gene variants in vivo.…”