APOL1

Detailed Information

APOL1 (Apolipoprotein L1) is a gene located at chromosome 22q12.3 in humans and encodes a secreted component of high-density lipoprotein (HDL). Orthologs of this gene are present in seven species, suggesting its function is evolutionarily conserved. The APOL1 protein belongs to the apolipoprotein L family, with a molecular weight of approximately 44 kDa. It consists of two major domains: an N-terminal membrane-binding domain and a C-terminal ion channel-forming domain. This unique structure allows APOL1 to insert into cellular membranes and form selective ion channels, providing the structural basis for its cytotoxic and pathogen-killing functions.

APOL1 displays tissue-specific expression in humans, with primary expression in the liver (RPKM 56.2), bladder (RPKM 39.7), and 21 other tissues. In the liver, APOL1 is synthesized by hepatocytes and secreted into the bloodstream, where it binds to apolipoprotein A-I (APOA1) to form a specific HDL subclass. This complex plays a key role in reverse cholesterol transport by facilitating the transfer of cholesterol from peripheral tissues to the liver. Importantly, APOL1 is also locally expressed in kidney podocytes, tubular epithelial cells, and vascular endothelial cells—a distribution closely associated with its role in kidney disease susceptibility.

The APOL1 gene has several transcript variants that encode different isoforms. Variant 1 (NP_003852.2) comprises 398 amino acids and includes a signal peptide and mature protein, while Variant 2 (NP_661308.2) lacks the sequence beyond amino acid 354. These isoforms differ in tissue distribution and function; Variant 2 is predominantly expressed in the kidney, whereas Variant 1 is enriched in plasma. These differential expression patterns contribute to the tissue specificity of APOL1-associated kidney diseases.

Figure 1. Proposed mechanisms by which APOL1 variants and gene dosage contribute to cytotoxicity, including roles for ER stress, PKR activation, and suPAR-mediated pathways. (Danielli M, et al., 2022)

Biological Functions and Pathogenic Mechanisms

The innate immune defense function of APOL1 is central to its evolutionary conservation. APOL1 can effectively kill Trypanosoma brucei, the parasite responsible for African sleeping sickness. The trypanolytic mechanism involves several steps:

1. Uptake: APOL1-HDL complexes are internalized by T. brucei via receptor-mediated endocytosis.
2. Lysosomal acidification: In acidic lysosomal conditions, APOL1 undergoes a conformational change exposing its membrane-binding domain.
3. Channel formation: APOL1 inserts into the lysosomal membrane to form anion-selective channels.
4. Ionic imbalance: Influx of chloride ions causes osmotic swelling and rupture of the lysosome.
5. Parasite death: Lysosomal contents are released into the cytoplasm, leading to parasite death.

Notably, the trypanolytic activity of APOL1 against T. b. rhodesiense is genotype-dependent. Only APOL1 proteins with the risk alleles (G1/G2) are effective against this virulent subspecies, explaining the positive selection pressure for these alleles in African populations.

In lipid metabolism, APOL1 participates in reverse cholesterol transport. By forming complexes with APOA1, it promotes ABCA1-mediated cholesterol efflux and reduces macrophage foam cell formation. APOL1 also regulates endothelial nitric oxide synthase (eNOS) activity, influencing vascular tone and contributing to vascular homeostasis.

Genetic Variants and Kidney Disease Risk

High-risk variants of APOL1 are primarily located in the C-terminal region and include two major alleles:

• G1 allele: Comprising two missense mutations (rs73885319, S342G; rs60910145, I384M)
• G2 allele: A six-base pair deletion (rs71785313, del388Y389)

These risk alleles are almost exclusively found in populations of African ancestry, reflecting evolutionary selection against African trypanosomiasis. The inheritance pattern follows an autosomal recessive model—kidney disease risk is significantly elevated only in individuals who inherit two high-risk alleles (homozygous or compound heterozygous). Epidemiological data indicate that about 13% of African Americans carry the high-risk genotype, with a lifetime kidney disease risk of at least 15%, over seven times higher than non-carriers.

Mechanisms of Kidney Pathogenesis

The pathogenesis of APOL1-related kidney disease involves several levels of cellular injury:

• Podocyte damage: High-risk APOL1 variants abnormally accumulate in glomerular podocytes, leading to mitochondrial dysfunction and reduced ATP production. Altered ion channel activity causes intracellular potassium efflux, activating caspase-3-mediated apoptosis.
• Endoplasmic reticulum stress: Misfolded variant APOL1 proteins accumulate in the ER, triggering the unfolded protein response (UPR) and ultimately podocyte apoptosis.
• Inflammatory response: In tubular epithelial cells, risk variants of APOL1 activate the NLRP3 inflammasome, increasing secretion of inflammatory cytokines such as IL-1β.
• Autophagy impairment: Risk variants interfere with autophagosome-lysosome fusion, leading to accumulation of damaged organelles.

These cellular insults manifest as glomerulosclerosis and tubulointerstitial fibrosis. It is important to note that APOL1-associated nephropathy typically requires a "second hit" to manifest clinically. As Professor Hui Ruhai has noted, "Not all patients carrying APOL1 risk alleles progress to end-stage renal disease. Modifier loci and environmental exposures such as viral infection or hypertension act as second hits."

Disease Spectrum and Epidemiology

The APOL1 high-risk genotype is associated with multiple forms of kidney disease:

• Focal segmental glomerulosclerosis (FSGS): Accounts for 70% of FSGS cases in African Americans and progresses twice as fast as non-APOL1-associated FSGS.
• HIV-associated nephropathy (HIVAN): Risk of kidney disease increases 29-fold in HIV-positive individuals with high-risk APOL1 genotypes.
• Hypertensive nephrosclerosis: In hypertensive African Americans, the high-risk genotype increases the risk of end-stage kidney disease (ESKD) fourfold.
• Lupus nephritis: Associated with specific pathologic transitions (e.g., class V membranous changes) and rapid renal function decline.

Clinically, APOL1-related nephropathy has characteristic features: early onset (typically before age 50), marked proteinuria (>3 g/24 h), and rapid eGFR decline (>5 mL/min/year), indicating a distinct pathological process.

Conclusion

As a uniquely human product of evolutionary adaptation, the APOL1 gene plays essential roles in host defense and lipid metabolism. Its high-risk variants significantly increase kidney disease susceptibility in people of African ancestry, particularly for glomerular disorders such as FSGS and HIVAN. With the discovery of protective variants and the development of targeted therapies, APOL1-related nephropathy is emerging as a model for precision nephrology. Future efforts should focus on dissecting gene-environment interactions and developing risk-stratified interventions to ultimately eliminate racial disparities in kidney health and achieve true health equity.