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

Jung Hwa Ryu, Mengyuan Ge, Sandra Merscher, Avi Rosenberg, Desante Marco, Roshanravan Hila, Koji Okamoto, Myung K. Shin, Maarten Hoek, Alessia Fornoni, B. Kopp ID Jeffrey

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0211559
JournalPloS one
Volume14
Issue number4
DOIs
StatePublished - Apr 1 2019

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apolipoproteins
Apolipoproteins
Macrophages
Transgenic Mice
macrophages
Cholesterol
kidneys
cholesterol
genetically modified organisms
Tissue
Kidney
mice
bone marrow
foam cells
Foam Cells
Bone
monocytes
Foams
tissues
Monocytes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice. / Ryu, Jung Hwa; Ge, Mengyuan; Merscher, Sandra; Rosenberg, Avi; Marco, Desante; Hila, Roshanravan; Okamoto, Koji; Shin, Myung K.; Hoek, Maarten; Fornoni, Alessia; Jeffrey, B. Kopp ID.

In: PloS one, Vol. 14, No. 4, e0211559, 01.04.2019.

Research output: Contribution to journalArticle

Ryu, JH, Ge, M, Merscher, S, Rosenberg, A, Marco, D, Hila, R, Okamoto, K, Shin, MK, Hoek, M, Fornoni, A & Jeffrey, BKID 2019, 'APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice', PloS one, vol. 14, no. 4, e0211559. https://doi.org/10.1371/journal.pone.0211559
Ryu, Jung Hwa ; Ge, Mengyuan ; Merscher, Sandra ; Rosenberg, Avi ; Marco, Desante ; Hila, Roshanravan ; Okamoto, Koji ; Shin, Myung K. ; Hoek, Maarten ; Fornoni, Alessia ; Jeffrey, B. Kopp ID. / APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice. In: PloS one. 2019 ; Vol. 14, No. 4.
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AU - Ge, Mengyuan

AU - Merscher, Sandra

AU - Rosenberg, Avi

AU - Marco, Desante

AU - Hila, Roshanravan

AU - Okamoto, Koji

AU - Shin, Myung K.

AU - Hoek, Maarten

AU - Fornoni, Alessia

AU - Jeffrey, B. Kopp ID

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