Dilemmas and challenges in apolipoprotein L1 nephropathy research

The purpose of this mini-review is to highlight some unresolved questions and controversies in the evolving story of apolipoprotein L1 (APOL1) nephropathy.

We highlight studies that introduce complexity in unraveling the mechanisms whereby APOL1 risk variant alleles cause disease. These include studies which support a possible protective role for the APOL1 GO nonrisk ancestral allele, and studies which explore the initiating events that may trigger other downstream pathways mediating APOL1 cellular injury. We also review studies that reconcile the perplexing findings regarding APOL1 anionic or cationic conductance, and pH dependency, and also studies that attempt to characterize the 3-dimensional structure of APOL1 C-terminal in APOL1 variants, as well as that of the serum resistance-associated protein. We also attempt to convey new insights from in-vivo and in-vitro models, including studies that do not support the differential toxicity of APOL1 renal risk variants and recapitulate the clinical variability of individuals at genotypic risk.

Along with major progress that had been achieved in the field of APOL1 nephropathy, controversies and enigmatic issues persist. It remains to be determined which of the pathways which have been demonstrated to mediate cell injury by ectopically expressed APOL1 risk variants in cellular and organismal models are relevant to human disease and can pave the way to potential therapy.