Apolipoprotein L1 (APOL1) nephropathy results from several podocyte dysfunctions involving morphological and motility changes, mitochondrial perturbations, inflammatory stress, and alterations in cation channel activity. I propose that this phenotype results from increased hydrophobicity of the APOL1 risk variants, which induces two distinct types of podocyte dysfunctions. On one hand, increased hydrophobic interactions with APOL3 cause intracellular variant isoforms to impair both APOL3 control of Golgi PI(4)P kinase-B (PI4KB) activity and APOL3 control of mitochondrial membrane fusion, triggering actomyosin reorganisation together with mitophagy and apoptosis inhibition (hit 1). On the other hand, increased hydrophobic interactions with the podocyte plasma membrane may cause the extracellular variant isoforms to activate toxic Ca2+ influx and K+ efflux by the TRPC6 and BK channels, respectively (hit 2), presumably due to APOL1-mediated cholesterol clustering in microdomains. I propose that hit 2 depends on low HDL-C/high extracellular APOL1 ratio, such as occurs in cell culture in vitro, or during type I-interferon (IFN-I)-mediated inflammation.
