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Elevation of Non-Classical (CD14+/lowCD16++) Monocytes Is Associated with Increased Albuminuria and Urine TGF-β1 in HIV-Infected Individuals on Stable Antiretroviral Therapy.

ABSTRACT: High rates of albuminuria are observed among HIV-infected individuals on stable antiretroviral therapy (ART). Though pro-inflammatory and pro-fibrotic responses are described as components of albuminuria in the general population, it is unclear how these responses are associated to albuminuria in ART-treated chronic HIV. We investigated the relationship of monocyte subsets and urine inflammatory and fibrotic biomarkers to albuminuria in ART-treated HIV-infected participants.Cross-sectional analyses were performed on Hawaii Aging with HIV-cardiovascular disease study cohort participants who were required at entry to be ≥40 years old and on ART ≥3 months. Monocyte subpopulations were determined in banked peripheral blood mononuclear cells (PBMC) using multi-parametric flow-cytometry. Entry random urine samples were assessed for albumin-to-creatinine ratios (UACR). Urine samples were measured for inflammatory and fibrotic biomarkers using Luminex technology.Among 96 HIV-infected subjects with measured UACR (87% male, 59% Caucasian, and 89% undetectable HIV RNA with median CD4 of 495.5 cells/μL), 18 patients (19%) had albuminuria. Non-classical (CD14low/+CD16++) monocytes were significantly elevated in subjects with albuminuria (p = 0.034) and were correlated to UACR (r = 0.238, p = 0.019). Elevated non-classical monocyte counts were significant predictors of worsening albuminuria, independent of traditional- and ART-associated risk factors (β = 0.539, p = 0.007). Urine TGF-β1 and collagen-IV were significantly higher in albuminuric compared to non-albuminuric participants (TGF-β1; p = 0.039 and collagen-IV; p = 0.042). Urine TGF-β1 was significantly correlated with non-classical monocyte counts (r = 0.464, p = 0.017).Alterations in monocyte subpopulations and urine pro-fibrotic factors may play a role in kidney dysfunction during chronic HIV infection and warrants further study.

SUBMITTER: Mitchell BI

PROVIDER: S-EPMC4838224 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Project description:PurposeThe effects of aqueous mediators possibly increasing the outflow resistance, transforming growth factor-β1 (TGF-β1), TGF-β2, autotaxin (ATX), and lysophosphatidic acid (LPA) on human trabecular meshwork (hTM) cells and monkey Schlemm's canal endothelial (SCE) cells were characterized and compared, and the effects of intracameral application of these mediators on intraocular (IOP) elevation were also examined.MethodsCells were treated with TGF-β1, TGF-β2, ATX, LPA, or vehicle, and mRNA and protein expression levels of α-SMA, COL1A1, fibronectin, β-catenin, and ZO-1 were examined with real-time quantitative PCR (RT-qPCR) or immunofluorescence analyses or both. The permeability of cell monolayers was measured by determining the transendothelial electrical resistance (TEER) or with the fluorescein isothiocyanate (FITC)-dextran permeability assay. IOP was evaluated in rabbit eyes after intracameral administration of the mediators.ResultsAll mediators induced upregulation of α-SMA, COL1A1, and fibronectin in hTM cells. The effect of TGF-β2 on mRNA expression of fibrotic markers was statistically significantly greater than that of TGF-β1. The effects of ATX and LPA indicated the time-dependent difference in the upregulation of α-SMA, COL1A1, and fibronectin. The TEER and FITC-dextran permeability of the SCE cells was evaluated after treatment with TGF-β1 and TGF-β2, but no statistically significant change was observed within 24 h. ATX and LPA also reduced permeability statistically significantly after 3 h and 0.5 h, respectively, and the effect of LPA was more rapid compared to that of ATX. Statistically significant IOP elevation was observed in rabbit eyes as early as 0.5-2.0 h after ATX and LPA treatment and at 24 h after treatment with TGF-β2.ConclusionsTGF-β2 and ATX and LPA regulate aqueous outflow by modulation of hTM cells and SCE cells, and differences in timing between the effects of each mediator were observed. ATX and LPA showed more rapid effects on IOP elevation than TGF-β2. It was suggested that TGF-β2 and ATX/LPA are involved in increases of IOP, but the timing and sustainability differ between mediators, and they may play specific roles in different glaucoma subtypes.

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Elevation of Non-Classical (CD14+/lowCD16++) Monocytes Is Associated with Increased Albuminuria and Urine TGF-β1 in HIV-Infected Individuals on Stable Antiretroviral Therapy.

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