APOL1 x GFM2

Apolipoprotein 1 (APOL1) risk variants (G1 and G2) are associated with focal segmental glomerulosclerosis (FSGS) in patients of African ancestry. The prevalence of APOL1 two risk variants is lower in Hispanics and very rare in European and Asian populations. APOL1 two risk variants in donor kidneys is associated with recipient kidney graft loss, however the effect of recipient risk variant in the kidney transplant outcome is unclear. Here, we present a late adolescent male with FSGS and end stage renal disease with one APOL1 risk variant (G2) who had immediate recurrence of FSGS in the post-KT period. There was an excellent response to few sessions of plasmapheresis and Rituximab with no further recurrence of FSGS in the 1 year follow-up period. It needs to be seen whether the recipient APOL1 single risk variant causes increased susceptibility to kidney graft loss on a long run via recurrent or de novo pathologies.

This article illustrates about Cation channel activity of apolipoprotein l1 is modulated by haplotype background.Three of these haplotypes, designated K1K, EIK, and EMR, account for the majority of protein isoforms in the human .KIK is the most prevalent worldwide.EIK is the most common haplotype in people of African ancestry and is absent from other populations; Gl and G2 variants are only naturally found in the EIK background.EMR thought to be of Neanderthal origin) is most frequently encountered in European populations.To test whether haplotype alters ion permease activity, we generated expression constructs encoding the GO, Gl, and G2 variants in die KIK, EIK, and EMR haplotypes, and assayed resulting proteins for ion permease activity and membrane associationOutput from the chloride-selective electrode is shown, starting widi 10μΜ KCl in buffered sucrose (pH 7.5).Protein and KCl loaded liposomes with no extravesicular KCl are added at the first arrow.Chloride ionophore is added at the second arrow, inducing lumen-pos. potential driving KCl efflux, limited by the K permeability.Triton X-IOO is added at the third arrow, releasing remaining intravesicular KC1.The maximal rate of fractional Cl release alter addition of ionophore is taken as the potassium permeability.Permeability conferred by each protein is equal to the rate in presence of protein minus the rate in the absence of protein.Thus, we find that naturally occurring haplotype-encoded isoforms of ApoLl have a significant effect on the cation channel activity without an effect on the chloride permease activity.The cation channel activity is greatest in the EIK (African) haplotype and is least in the EMR (Neanderthal) haplotype.The relative differences in cation channel activity among the wildtype and disease-associated variants is independent of haplotype: in all three haplotypes, the disease-associated variants have approx. double the cation channel activity ofthe wild type.

We evaluated alterations in the structural configurations of channels and activation of nucleotide‐binding domain, leucine‐rich‐containing family, pyrin domain‐containing‐3 (NLRP3) inflammasome formation in apolipoprotein L1 (APOL1) risk and nonrisk milieus. APOL1G1‐ and APOL1G2‐expressing podocytes (PD) displayed enhanced K+ efflux, induction of pyroptosis, and escalated transcription of interleukin (IL)‐1β and IL‐18. APOL1G1‐ and APOL1G2‐expressing PD promoted the transcription as well as translation of proteins involved in the formation of inflammasomes. Since glyburide (a specific inhibitor of K+ efflux channels) inhibited the transcription of NLRP3, IL‐1β, and IL‐18, the role of K+ efflux in the activation of inflammasomes in APOL1 risk milieu was implicated. To evaluate the role of structural alterations in K+ channels in plasma membranes, bioinformatics studies, including molecular dynamic simulation, were carried out. Superimposition of bioinformatics reconstructions of APOL1G0, G1, and G2 showed several aligned regions. The analysis of pore‐lining residues revealed that Ser342 and Tyr389 are involved in APOL1G0 pore formation and the altered conformations resulting from the Ser342Gly and Ile384Met mutation in the case of APOLG1 and deletion of the Tyr389 residue in the case of APOL1G2 are expected to alter pore characteristics, including K+ ion selectivity. Analysis of multiple membrane (lipid bilayer) models of interaction with the peripheral protein, integral membrane protein, and multimer protein revealed that for an APOL1 multimer model, APOL1G0 is not energetically favorable while the APOL1G1 and APOL1G2 moieties favor the insertion of multiple ion channels into the lipid bilayer. We conclude that altered pore configurations carry the potential to facilitate K+ ion transport in APOL1 risk milieu.