ApoL1 renal risk variants induce aberrant THP-1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase-2

Abstract

Apolipoprotein L1 ( ApoL1) genetic variants are strongly associated with kidney diseases. We investigated the role of ApoL1 variants in monocyte differentiation and eicosanoid production in macrophages, as activated tissue macrophages in kidney might contribute to kidney injury. In human monocyte THP-1 cells, transient overexpression of ApoL1 (G0, G1, G2) by transfection resulted in a 5- to 11-fold increase in CD14 and CD68 gene expression, similar to that seen with phorbol-12-myristate acetate treatment. All ApoL1 variants caused monocytes to differentiate into atypical M1 macrophages with marked increase in M1 markers CD80, TNF, IL1B, and IL6 and modest increase in the M2 marker CD163 compared with control cells. ApoL1-G1 transfection induced additional CD206 and TGFB1 expression, and ApoL1-G2 transfection induced additional CD204 and TGFB1 expression. Gene expression of prostaglandin E (PGE) synthase and thromboxane synthase and both gene and protein expression of cyclooxygenase-2 (COX-2) were increased by ApoL1-G1 and -G2 variants compared with -G0 transfection. Higher levels of PGE and thromboxane B, a stable metabolite of thromboxane A, and transforming growth factor (TGF)-β1 were released into the supernatant of cultured THP-1 cells transfected with ApoL1-G1 and -G2, but not -G0. The increase in PGE, thromboxane B, and TGF-β1 was inhibited by COX-2-specific inhibitor CAY10404 but not by COX-1-specific inhibitor SC-560. These results demonstrate a novel role of ApoL1 variants in the regulation of monocyte differentiation and eicosanoid metabolism, which could modify the immune response and promote inflammatory signaling within the local targeted organs and tissues including the kidney.

Macrophage polarization in innate immune responses contributing to pathogenesis of chronic kidney disease

“…2 Potential roles of ApoL1 in macrophage polarization. Based on our recent in vitro observation [ 60 ], overexpression of all APOL1 variants differentiate macrophages into an atypical M1 state with a marked increase in M1 markers CD80 (not shown), TNF , IL1β , and IL6 . Renal risk variants induce additional TGF-β1 and CD204 (not shown) or CD206 (not shown) expression.…”

“…In APOL1 overexpressing THP-1 macrophages, all three APOL1 isoforms cause monocytes to differentiate into atypical M1 macrophages (Fig. 2 ) with a marked increase in M1 markers CD80 , TNF , IL1B , and IL6 and a modest increase in the M2 marker CD163 [ 60 ]. It seems this atypical M1 polarization itself is not sufficient to induce CKD, because APOL1-G0 induces this atypical M1 polarization as well [ 60 ].…”

“…2 ) with a marked increase in M1 markers CD80 , TNF , IL1B , and IL6 and a modest increase in the M2 marker CD163 [ 60 ]. It seems this atypical M1 polarization itself is not sufficient to induce CKD, because APOL1-G0 induces this atypical M1 polarization as well [ 60 ]. Over-expression of APOL1 risk variants increases gene expression of the pro-inflammatory cytokines such as TNF, IL-1β and IL-6; increases gene and protein expression of TGF-β; and increases production of prostaglandin E2 [ 60 ].…”

Association of Genetic Polymorphisms of TGF-β1, HMOX1, and APOL1 With CKD in Nigerian Patients With and Without HIV

“…16 There is some basis for theorizing a direct relationship between APOL1 renal risk expression and TGF-β1 in the inflammatory cascades leading to tissue fibrosis. One cell culture study documented that in an APOL1 G1 and G2 (but not G0) context, there was increased TGF-β1 activity in T-helper cells through a cyclooxygenase-2-dependent pathway, 17 raising the possibility that APOL1 and TGF-β1 may be interrelated in the orchestration of renal fibrosis in CKD pathogenesis. The TGF-β1 single-nucleotide polymorphisms (SNPs) rs1800469, rs1800470, and rs1800471 have been found to be associated with CKD in some climes.…”

APOL1 and kidney cell function

“…These findings suggest that APOL1 RRVs do not influence HIV infection or progression in individuals with African ancestry. However, because of the alteration of the macrophage differentiation profile in APOL1 RRV milieu, an accelerated progression of tubulointerstitial disease remains a possibility in patients with HIVAN (63).…”