APOL1: The Balance Imposed by Infection, Selection, and Kidney Disease

Abstract

Chronic kidney disease (CKD) affects millions of people and constitutes a major health and financial burden worldwide. People of African descent are at an increased risk of developing kidney disease, which is mostly explained by two variants in the Apolipoprotein L1 (APOL1) gene that are found only in people of west African origin. It is hypothesized that these variants were genetically selected due to the protection they afford against African sleeping sickness, caused by the parasite Trypanosoma brucei. Targeting mutant APOL1 could have substantial therapeutic potential for treating kidney disease. In this review, we will describe the intriguing interplay between microbiology, genetics, and kidney disease as revealed in APOL1-associated kidney disease, discuss APOL1-induced cytotoxicity and its therapeutic implications.

Keywords: Apolipoprotein 1; chronic kidney disease; genetics.

Figure 1. Transgenic expression of podocyte specific APOL1 induces kidney disease in mice

The doxycycline inducible (rtTA) system was used to generate mice with podocyte specific conditional inducible APOL1 expression. Transgene expression was controlled by doxycycline and the nephrin (NPHS1) rtTA promoter was used to drive podocyte specific expression. Either APOL1 reference (G0) or risk allele (G1 or G2) was expressed (TRE-APOL1). When exposed to doxycycline, transgenic mice expressing risk allele APOL1 developed kidney disease including functional (proteinuria and renal failure) and structural (glomerulosclerosis and foot process effacement) changes, similar to the human kidney disease. Transgenic mice expressing the reference allele did not develop disease.

Figure 2. Environmental hits are necessary for disease development

Most people with two APOL1 risk alleles will not develop disease. A second hit is required to induce kidney disease in high risk genotype people. Environmental factors serve as second hits. Viral infections, most likely via an interferon mediated mechanism, present an important second hit for kidney disease development. HIV is a well-established second hit. Multiple studies suggest that environmental factors induce kidney disease by increasing risk variant APOL1 transcript and protein expression in podocytes. Environmental triggers such as viral infections induce interferon expression, which then increases APOL1 protein expression above a certain critical threshold that leads to progressive CKD. People with one risk allele have a lower expression of risk variant that are less likely to reach this threshold.

Figure 3. Intracellular mechanisms of APOL1-induced cytotoxicity

(A) In wild type podocytes, reference allele APOL1 does not affect endocytosis and autophagy. Autophagy inhibits pyroptosis, and mitochondrial and ER functions are unperturbed. (B) Upon exposure to a second hit, a cascade of events is initiated in podocytes expressing two APOL1 risk alleles that culminate in podocyte loss and dedifferentiation. APOL1 inserts into membranes and creates anion (when exposed to low pH, e.g. in the lysosome) or cation channel (when exposed to neutral pH, e.g. in the plasma membrane). These channels mediate ion fluxes that induce osmotic swelling and further activate toxic intracellular pathways (top panel). Due to defective endo-lysosomal trafficking and impaired acidification of endocytic vacuoles, there is a defect in autophagosome maturation resulting in an autophagy block and accumulation of endocytic vacuoles (middle panel). Consequently, various intracellular pathways are activated; including stress activated protein kinase signaling, mitochondrial and endoplasmic reticulum damage and inflammasome activation, resulting in caspase1-mediated inflammatory cell death, pyroptosis. Pyroptosis involves the release of IL1 and IL18, DNA fragmentation, and by a positive feedback loop can increase APOL1 protein expression and could further enhance cytotoxicity (bottom panel).