Apolipoprotein L1 and Kidney Disease in African Americans

Abstract

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. Although 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 present in only 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.

Keywords: APOL1; African American; apolipoprotein L1; kidney disease.

Figure I. Distribution of the G1 and G2 APOL1 variants across Africa

Allele frequencies of the G1 and G2 variants are indicated as blue and green wedges, respectively. Circle size reflects the number of individuals genotyped: small, <10 individuals/20 chromosomes; medium, 10–100 individuals/ 20–200 chromosomes; large, >100 individuals/200 chromosomes. Countries are shaded according to the subspecies of Trypanosoma brucei that cause African sleeping sickness. Darker green, gambiense types 1 and 2; light green, gambiense type 1; pink, both rhodesiense and gambiense type 1; purple, rhodesiense. Reproduced from reference (42).

Figure 1. APOL1 mechanism of cell death

APOL1 causes cell death in kidney HEK293 cells and risk variant APOL1 is far more toxic than WT APOL1. Risk variant cell death is accompanied by cellular potassium depletion and activation of MAP kinase pathways. Replacing media in the extracellular space with high-K⁺ media reduces cytotoxicity, whereas replacing extracellular sodium with a large cation that does not cross the cell membrane such as N-methyl-d-glucamine (NMDG) does not reduce cytotoxicity, suggesting that K⁺ efflux may be the primary event leading to APOL1-mediated cell death. MAP kinase inhibitors also reduce cell death, pointing toward known pathways, whereby stress caused by K⁺ depletion can activate cell death. Whereas K+ efflux alone would be expected to cause cell shrinkage, cell death is instead accompanied by cell swelling, suggesting that sodium may be entering the cell in response to K⁺ efflux. It is not clear whether this occurs through ApoL1 channels or by other routes, and Na⁺ influx is not necessary for cell death at least in this model system, so important questions remain to be answered. (51)

Figure 2. Properties of the APOL1 ion channel

ApoL1 acts as an ion channel to kill trypanosomes, and the same mechanism may be important for kidney injury. Left: In a lipid bilayer system, ApoL1 channel activity is not seen at normal pH prior to activation by an acid environment. ApoL1 is postulated to form multimers as an explanation for why the protein is a toxic, gain-of-function mutation, yet is inherited recessively. In other words, wild-type ApoL1 may neutralize the toxicity of the risk variant. Whether multimers might form prior to lipid bilayer entry or after entry is unknown. Center: At low pH, APOL1 can insert in a lipid bilayer and lead to low-level cation flux. Right: Once the APOL1 is inserted in the membrane, a return to neutral pH leads to a huge increase in ion flux capacity. The trypanosome virulence factor SRA does not block the acid-dependent membrane entry but does block the enhanced conductance caused by pH neutralization, posing the hypothesis that the rise in pH leads to the APOL1 C-terminus inserting into the membrane in an SRA-preventable fashion. One leading hypothesis for the greater toxicity of risk-variant than WT APOL1 is that either genotype-specific cellular APOL1 binding partners prevent WT APOL1 from inserting in the kidney cell membrane or that risk variant specific binding partners are necessary for trafficking to the site of toxicity or for channel activation. (50)