Inflammatory proteolysis generates pathogenic APOL1 fragments with distinct intracellular toxicities in podocytes derived from children with HIV associated nephropathy.

The study investigates the mechanisms behind HIV-associated nephropathy (HIVAN) by examining the role of APOL1 risk variants in podocyte injury. Researchers employed urine-derived podocytes from children with HIVAN, along with endogenous APOL1 reporter cell lines, to uncover a previously unexplored pathway of inflammatory, cathepsin-dependent APOL1 proteolysis.

The findings revealed that endogenous APOL1 cleavage was present in patient-derived podocytes, while reporter cell lines allowed for the identification and functional characterization of both N-terminal and C-terminal APOL1 fragments. The nuclear N-terminal fragment was discovered to activate inflammatory transcriptional programs and contribute to podocyte injury, whereas the membrane-associated C-terminal fragment mediated membrane toxicity, which remained susceptible to pharmacologic inhibition by inaxaplin.

The study concludes that cathepsin S directly cleaves APOL1 in vitro, establishing a link between inflammatory signaling and APOL1 fragmentation. This research highlights inflammatory APOL1 proteolysis as a mechanism that partitions APOL1 toxicity into distinct pathogenic programs, suggesting APOL1 processing as a potential therapeutic target for HIV-associated and other APOL1-mediated kidney diseases.