Immunity unmasks APOL1 in collapsing glomerulopathy
Authors: Bairbre A. McNicholas, Peter J. Nelson
Journal: Kidney International (2015)

Collapsing glomerulopathy predominantly afflicts patients of African ancestry, often first presenting after the immune system is engaged by another disorder. Nichols et al. now show that collateral induction of pathogenic APOL1 allelic variants in podocytes by the ongoing immune response may be the long-sought-after explanation for the development of collapsing glomerulopathy in these patients. Collapsing glomerulopathy predominantly afflicts patients of African ancestry, often first presenting after the immune system is engaged by another disorder. Nichols et al. now show that collateral induction of pathogenic APOL1 allelic variants in podocytes by the ongoing immune response may be the long-sought-after explanation for the development of collapsing glomerulopathy in these patients. A major breakthrough in understanding the increased risk for podocyte injury and concomitant glomerular disease in subjects of African ancestry came with studies linking genetic variations in APOL1 with focal segmental glomerulosclerosis, hypertension-attributed end-stage renal disease, and collapsing glomerulopathy (CG) associated with HIV infection.1Genovese G. Friedman D.J. Pollak M.R. APOL-1 variants and kidney disease in people of recent African ancestry.Nat Rev Nephrol. 2013; 9: 240-244Crossref PubMed Scopus (70) Google Scholar Genetic associations were found to cluster in the last exon of APOL1, with the strongest signal for an allelic variant (G1) consisting of two non-synonymous coding mutations (S342G and I384M), and a second allelic variant (G2) coding for a two-amino acid deletion (N388 and Y389) at the C-terminal end of the ApoL1 protein.1Genovese G. Friedman D.J. Pollak M.R. APOL-1 variants and kidney disease in people of recent African ancestry.Nat Rev Nephrol. 2013; 9: 240-244Crossref PubMed Scopus (70) Google Scholar However, the pathogenic mechanisms that unmask the genetic susceptibilities to podocyte injury from these APOL1 allelic variants are largely unknown. APOL1 is restricted to humans and several nonhuman primates, and previous studies suggest that basal expression of ApoL1 protein occurs in endothelial cells, mononuclear phagocytes, cells of the placenta, and neurons of the prefrontal cortex.2Vanhollebeke B. Pays E. The function of apolipoproteins L.Cell Mol Life Sci. 2006; 63: 1937-1944Crossref PubMed Scopus (100) Google Scholar Within the kidney, ApoL1 protein has been detected in podocytes, endothelial cells, and proximal tubular epithelial cells.3Madhavan S.M. O'Toole J.F. Konieczkowski M. et al.APOL-1 localization in normal kidney and nondiabetic kidney disease.J Am Soc Nephrol. 2011; 22: 2119-2128Crossref PubMed Scopus (190) Google Scholar ApoL1 protein also circulates as a minor component of high-density lipoprotein particles in blood, where it is thought to function in the transport and metabolism of lipids.2Vanhollebeke B. Pays E. The function of apolipoproteins L.Cell Mol Life Sci. 2006; 63: 1937-1944Crossref PubMed Scopus (100) Google Scholar Under normal conditions, ApoL1 protein appears to be expressed at low levels in these various cell types. Before the discovery that its G1 and G2 allelic variants are associated with specific glomerular diseases, APOL1 was known to encode an important immune effector. In trypanosome infections, ApoL1 protein plays a critical role as a trypanolytic factor during the innate and adaptive phases of the immune response to infection to suppress parasitic replication and spreading.4Namangala B. Contribution of innate immune responses towards resistance to African trypanosome infections.Scand J Immunol. 2012; 75: 5-15Crossref PubMed Scopus (14) Google Scholar,5Drennan M.B. Stijlemans B. Van Den Abbeele J. et al.The induction of a type 1 immune response following a Trypanosoma brucei infection is MyD88 dependent.J Immunol. 2005; 175: 2501-2509Crossref PubMed Scopus (113) Google Scholar Several trypanosome-derived molecules act as innate immune Toll-like receptor (TLR) agonists to upregulate the expression of ApoL1 protein and proinflammatory cytokines by surveying mononuclear phagocytes.4Namangala B. Contribution of innate immune responses towards resistance to African trypanosome infections.Scand J Immunol. 2012; 75: 5-15Crossref PubMed Scopus (14) Google Scholar,5Drennan M.B. Stijlemans B. Van Den Abbeele J. et al.The induction of a type 1 immune response following a Trypanosoma brucei infection is MyD88 dependent.J Immunol. 2005; 175: 2501-2509Crossref PubMed Scopus (113) Google Scholar Moreover, as intracellular pathogens, trypanosomes are T-helper type 1 (Th1)-polarizing, and Th1 cytokines (interferons and tumor necrosis factor-α) elaborated during the innate and adaptive phases of Th1 responses also upregulate the expression of ApoL1 protein.4Namangala B. Contribution of innate immune responses towards resistance to African trypanosome infections.Scand J Immunol. 2012; 75: 5-15Crossref PubMed Scopus (14) Google Scholar,5Drennan M.B. Stijlemans B. Van Den Abbeele J. et al.The induction of a type 1 immune response following a Trypanosoma brucei infection is MyD88 dependent.J Immunol. 2005; 175: 2501-2509Crossref PubMed Scopus (113) Google Scholar This immune-regulated expression of ApoL1 protein helps to prevent chronic, persistent trypanosomiasis.4Namangala B. Contribution of innate immune responses towards resistance to African trypanosome infections.Scand J Immunol. 2012; 75: 5-15Crossref PubMed Scopus (14) Google Scholar,5Drennan M.B. Stijlemans B. Van Den Abbeele J. et al.The induction of a type 1 immune response following a Trypanosoma brucei infection is MyD88 dependent.J Immunol. 2005; 175: 2501-2509Crossref PubMed Scopus (113) Google Scholar On the basis of this prior knowledge, Nichols et al.6Nichols B. Jog P. Lee J.H. et al.Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.Kidney Int. 2014; 86 (this issue)Google Scholar (this issue) reason that the susceptibility to podocyte injury from the G1 and G2 APOL1 allelic variants may be unmasked by immune responses that induce expression of the corresponding ApoL1 protein variants within the glomerulus. To address this possibility, the authors focus on CG, a glomerular disease offering one of the most robust clinical–pathological correlates linking antecedent Th1-polarizing disorders to podocyte injury.7Albaqumi M. Soos T.J. Barisoni L. et al.Collapsing glomerulopathy.J Am Soc Nephrol. 2006; 17: 2854-2863Crossref PubMed Scopus (127) Google Scholar The authors take advantage of a previously reported clinical–pathological correlate between pharmacological use of interferons (IFNs) and the development of CG in a cohort of subjects of African descent, and show that these subjects are homozygous for the APOL1 allelic variants conferring susceptibility to CG. However, the authors do not show in the archival biopsy tissue from this cohort that expression of ApoL1 protein is up- or downregulated in diseased glomeruli in vivo, as might be expected if IFN-responsive glomerular cells are present or lost, respectively, at the time of biopsy. Notwithstanding, the authors do address in vitro whether the expression of ApoL1 protein is regulated by IFNs in the glomerular cells that are injured in CG. The authors show that IFNs and TLR3 agonists that induce IFNs markedly upregulate the expression of ApoL1 protein in cultured human podocytes and endothelial cells. The authors further carefully establish the signaling and transcriptional pathways (Figure 1) responsible for this regulation, and find that both IFN-dependent and TLR3-dependent, IFN-independent pathways are operable. The relevance of this immune-regulated expression to the development of CG is suggested by the authors' results showing that ectopic expression of the ApoL1 variant proteins caused greater death of human embryonic kidney cells as compared with non-variant ApoL1 protein. This is intriguing in that experimental approaches to induce injury and death of podocytes in some rodent models have resulted in glomerular pathology resembling CG in humans.7Albaqumi M. Soos T.J. Barisoni L. et al.Collapsing glomerulopathy.J Am Soc Nephrol. 2006; 17: 2854-2863Crossref PubMed Scopus (127) Google Scholar One notable strength of the authors' approach is that their study of the interplay of immune factors, APOL1 alleles, and ApoL1 protein in CG utilizes only human systems. Currently, much of the prior research on CG using rodent systems to decipher molecular mechanisms is now being questioned as to its applicability to humans based on the fact that APOL1 alleles and ApoL1 protein are absent in rodents. This is particularly true for CG associated with HIV infection, in which the G1 and G2 APOL1 allelic variants markedly increase susceptibility to CG in humans,1Genovese G. Friedman D.J. Pollak M.R. APOL-1 variants and kidney disease in people of recent African ancestry.Nat Rev Nephrol. 2013; 9: 240-244Crossref PubMed Scopus (70) Google Scholar whereas genetic risk in rodent models is unrelated to APOL1. While providing key mechanistic insights, the study by Nichols et al.6Nichols B. Jog P. Lee J.H. et al.Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.Kidney Int. 2014; 86 (this issue)Google Scholar does leave several important questions regarding the role of ApoL1 protein variants in CG unanswered. First, CG is characterized pathologically as a proliferative lesion with increased numbers of diseased glomerular epithelial cells, not as a cytopenic lesion as would be expected if ApoL1 protein variants simply cause cell death.7Albaqumi M. Soos T.J. Barisoni L. et al.Collapsing glomerulopathy.J Am Soc Nephrol. 2006; 17: 2854-2863Crossref PubMed Scopus (127) Google Scholar One possible explanation for this paradox may be that ApoL1 protein variants are similarly upregulated in glomerular parietal epithelial cells or other potential podocyte precursors, resulting in hyperplastic phenotypes specific to these lineages and disrupting their ability to healthily replace injured podocytes. Second, paracrine cross-talk between glomerular endothelial cells and podocytes secondary to expression of ApoL1 protein variants may result in CG;7Albaqumi M. Soos T.J. Barisoni L. et al.Collapsing glomerulopathy.J Am Soc Nephrol. 2006; 17: 2854-2863Crossref PubMed Scopus (127) Google Scholar this possibility is not addressed by the authors despite their study of both cell types. Lastly, the Th1 cytokines that upregulate the expression of ApoL1 protein have independent effects on podocytes and endothelial cells;8Anders H.-J. Lichtnekert J. Interferon-α AllamR and -β in kidney inflammation.Kidney Int. 2010; 77: 848-854Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,9Bruggeman L. Drawz P.E. Kahoud N. et al.TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α.Lab Invest. 2011; 91: 413-425Crossref PubMed Scopus (60) Google Scholar when integrated with the effects of ApoL1 protein variants, the emergent cellular phenotypes of these cells may differ significantly from that created by ectopic expression of ApoL1 protein variants alone in the absence of Th1 cytokines. Thus, in vitro studies that immunologically challenge human podocytes or endothelial cells derived directly from subjects harboring the APOL1 allelic variants may better elucidate the pathogenesis of CG in vivo. In any respect, the study by Nichols et al.6Nichols B. Jog P. Lee J.H. et al.Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.Kidney Int. 2014; 86 (this issue)Google Scholar marks an exciting step forward in understanding how immunity may unmask the susceptibility to CG posed by APOL1 allelic variants that confer risk for podocyte injury.