Apolipoprotein L1 and mechanisms of kidney disease susceptibility

Abstract

Purpose of review: Allelic variants in the gene for apolipoprotein L1 (APOL1), found only in individuals of African ancestry, explain a majority of the excess risk of kidney disease in African Americans. However, a clear understanding how the disease-associated APOL1 variants cause kidney injury and the identity of environmental stressors that trigger the injury process have not been determined.

Recent findings: Basic mechanistic studies of APOL1 biochemistry and cell biology, bolstered by new antibody reagents and inducible pluripotent stem cell-derived cell systems, have focused on the cytotoxic effect of the risk variants when APOL1 gene expression is induced. Since the APOL1 variants evolved to alter a key protein-protein interaction with the trypanosome serum resistance-associated protein, additional studies have begun to address differences in APOL1 interactions with other proteins expressed in podocytes, including new observations that APOL1 variants may alter podocyte cytoskeleton dynamics.

Summary: A unified mechanism of pathogenesis for the various APOL1 nephropathies still remains unclear and controversial. As ongoing studies have consistently implicated the pathogenic gain-of-function effects of the variant proteins, novel therapeutic development inhibiting the synthesis or function of APOL1 proteins is moving toward clinical trials.

Trial registration: ClinicalTrials.gov NCT04340362 NCT04269031.

Conflict of interest statement

Conflict of Interest

The authors have received royalty payments for the commercial use of APOL1 transgenic mouse models.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1.. Proposed plasma membrane structure of the APOL1 channel.

A. The original protein domain structure for APOL1 including the location of the G1 and G2 polymorphisms in the serum response associated (SRA) binding domain. Protein domain shading is the same for all panels, and numbers are the amino acids numbering for the full-length 398 amino acid protein. B. Working model proposed by Schaub et al. (11). C. Working model proposed by Gupta et al. (9). Both models have the majority of the pore-forming domain as extracellular, with two, full-pass transmembrane helices. The Schaub model has two additional full-pass transmembrane regions, with the fourth transmembrane segment as the pore-lining domain that mediates pH sensitivity. The Gupta model proposes the majority of the membrane addressing domain to be on the extracellular surface, but this domain was inaccessible for antibody recognition, suggesting this region was sterically blocked by possibly another protein. Part of this region was predicted to loop into the membrane but not span the membrane. The linker region was assessed to be on the extracellular surface, which is opposite of the Schaub model predictions. Both models propose the SRA-binding domain to be partially inserted into the membrane, with the carboxy-terminus extending into the extracellular space.