APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice

Abstract

Apolipoprotein L1 ( APOL1 ) genetic variants G1 and G2, compared to the common allele G0, are major risk factors for non-diabetic kidney disease in African descent populations. APOL1 is a minor protein component of HDL, as well as being expressed in podocytes and vascular cells. Reverse cholesterol transport involves the transport of cholesterol to HDL by cellular ATP-binding cassette; ABCA1 and ABCG1 with subsequent delivery from peripheral tissues to the liver. With impaired reverse cholesterol transport, lipid accumulation occurs and macrophages morphologically transform into foam cells, releasing inflammatory factors. We asked whether the APOL1 risk variants alter peripheral cholesterol metabolism and specifically affect macrophage cholesterol efflux. Tissues and bone marrow (BM)-derived monocytes were isolated from wild-type mice (WT) and from BAC/APOL1 transgenic (APOL1-G0, APOL1-G1, and APOL1-G2) mice, which carry a bacterial artificial chromosome that contains the human APOL1 genomic region. Monocytes were differentiated into macrophages using M-CSF, and then polarized into M1 and M2 macrophages. Cholesterol content, cholesterol efflux, and ABCA1 and ABCG1 mRNA expression were measured. Kidney, spleen, and bone marrow-derived macrophages from APOL1-G1 and -G2 mice showed increased cholesterol accumulation and decreased ABCA1 and ABCG1 mRNA levels. BM-derived macrophages from APOL1-G1 and -G2 mice showed significantly reduced cholesterol efflux compared to WT or APOL1-G0 macrophages. Taken together, the evidence suggests that APOL1-G1 and -G2 risk variants impaired reverse cholesterol transport through decreased expression of cholesterol efflux transporters suggesting a possible mechanism to promote macrophage foam cell formation, driving inflammation in the glomerulus and renal interstitium.

APOL1 is not expressed in proximal tubules and is not filtered

“…None of the BAC-APOL1 mice spontaneously developed proteinuria ( Fig. 1D), which is consistent with the original description of these mouse models (13,14). When proteinuria was induced by interbreeding with a model of HIV-associated nephropathy ( Fig.…”

“…Three transgenic mouse lines expressing a human bacterial artificial chromosome (BAC) encompassing the entire APOL1 genomic region for either the G0, G1, or G2 alleles have been described (13,14). These mice express APOL1 under native gene regulatory regions and appear to replicate the gene expression pattern observed in humans.…”

“…Mouse Models: Three transgenic mouse lines expressing a 47kb human BAC encompassing the promoter and coding regions of the human APOL1 gene for each G0, G1, or G2 alleles (BAC-APOL1-G0, BAC-APOL1-G1, or BAC-APOL1-G2) were developed at MSD Research Laboratories and have been previously described (13,14). BAC-APOL1 transgenic lines were backcrossed to FVB/Nj for this study.…”

The Role and Function of HDL in Patients with Chronic Kidney Disease and the Risk of Cardiovascular Disease

“…Moreover, in a study using the population from the Women's Health Initiative, no association was found between the high-risk genotype and cardiovascular event precursors, including left ventricular hypertrophy [137]. Ryu et al [141] showed that APOL1-G1 and -G2 genetic variants were associated with higher intracellular cholesterol content, ABCA1 and ABCG1 suppression, and, in consequence, with reduced reverse cholesterol transport. The results of their study suggest that impaired cholesterol efflux capacity observed in APOL1 renal risk variant macrophages may stimulate, in vivo, the formation of foam cells.…”

APOL1 and kidney cell function

“…However, the involved mechanism of the generation of foam cells in FSGS is far from clear. In a recent report, Ryu et al (85) showed that expression of APOL1 RRVs diminishes cholesterol efflux in macrophages, resulting in the alteration of their phenotype. These investigators harvested monocytes from the kidney, spleen, and bone marrow from wild-type, APOL1 G0, APOL1 G1, and APOL1 G2 transgenic mice.…”