Development of higher rates of non-diabetic glomerulosclerosis (GS) in African Americans has been attributed to two coding sequence variants (G1 and G2) in the APOL1 gene. To date, the cellular function and the role of APOL1variants (Vs) in GS are still unknown. In this study, we examined the effects of over expressing wild type (G0) and kidney disease risk variants (G1 and G2) of APOL1 in human podocytes using a lentivirus expression system. Interestingly, G0 inflicted podocyte injury only at a higher concentration; however, G1 and G2 promoted moderate podocyte injury at lower and higher concentrations. APOL1Vs expressing podocytes displayed diffuse distribution of both Lucifer yellow dye and cathepsin L as manifestations of enhanced lysosomal membrane permeability (LMP). Chloroquine attenuated the APOL1Vs-induced increase in podocyte injury, consistent with targeting lysosomes. The chloride channel blocker, DIDS prevented APOL1Vs- induced injury indicating a role for chloride influx in osmotic swelling of lysosomes. Direct exposure of non-infected podocytes with conditioned media from G1 and G2 expressing podocytes also induced injury, suggesting a contributory role of the secreted component of G1 and G2 as well. Adverse host factors (AHFs) such as hydrogen peroxide, hypoxia, tumor necrosis factor-α, and puromycin aminonucleoside augmented APOL1- and APOL1Vs-induced podocyte injury; while the effect of HIV on podocyte injury was overwhelming under conditions of APOLVs expression. We conclude that G0 and G1 and G2 APOL1 variants have potential to induce podocyte injury in a manner which is further augmented by AHFs, with HIV infection being especially prominent.
- Aopl1 risk variants
- Chronic kidney diseaes
- lu=ysosomal permeability
- Copyright © 2013, American Journal of Physiology - Renal Physiology