Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1

Abstract

Apolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and toll-like receptor agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IRF-3 dependent pathway. Using pharmacological inhibitors, shRNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-kB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that anti-viral pathways may be an important inducer of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment.

Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: Relevance to trypanosome lysis

“…A prediction of this model is that swelling and lysis should be prevented simply by balancing the internal osmotic pressure with plasma-membrane impermeant solutes added to the extracellular fluid. Indeed, it was reported that sucrose could prevent lysis by human serum (22) and that large ions including tetramethylammonium + and gluconate − could prevent lysis by TLF1 (23,24). Such a model would also explain the increase in cation permeability of the parasite plasma membrane, observed within 15 min of exposure to human serum (23).…”

“…These data are allied to a cytoplasmic-swelling model of trypanosome lysis that is contingent with endocytic recycling of APOL1 and the formation of cation-selective channels in the parasite plasma membrane. Confirmation of this model will require additional studies; nevertheless, the possibility that APOL1 generates cytolytic lesions in plasma membranes may inform speculation about the potential role of APOL1 in mediating human cell death (42), as well as hypotheses regarding the potential pathophysiological impact of human APOL1 variants that are associated with kidney disease (19,22).…”

“…Two such human variants have been identified: the first, G1, is defined by two point mutations (S342G and I384M), one of which (I384M) was found to reduce binding affinity for SRA; the second, G2, is defined by a two-residue deletion (N388 and Y389) that prevents SRA binding (19). However, the G1-and G2-coding variants, found only among individuals of recent African ancestry, are strongly associated with chronic kidney disease in African Americans (20,21) and are thought to increase the propensity of APOL1 to cause tissue damage and human cell death (19,22).…”

Focal Segmental Glomerulosclerosis

“…One setting in which the adaptive processes drive APOL1 FSGS is perhaps the report that APOL1 variants are associated with proteinuric sickle cell nephropathy (97), although a systematic study of kidney histology in APOL1-associated sickle nephropathy is still lacking. APOL1 high-risk alleles are strongly associated with collapsing glomerulopathy in several settings: (1) HIVAN, in which 72% have two APOL1 high-risk alleles (83), and (2) the use of exogenous IFN (98) and in lupus (99).…”

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

“…Upon further investigation, we found that this association between APOL1 high‐risk status and incident HF was only slightly attenuated by hypertension and not at all by kidney function markers. APOL1 expression is driven by inflammation, and its protein product has been found in endothelial and vascular smooth muscle cells within the kidney 16, 55. Among individuals with decompensated HF, different variants in the APOL1 gene have been associated with differential responsiveness to furosemide‐based diuretic regimens, and whether differences in response to medications may explain observed associations is not known 56.…”