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- W3149604645 abstract "Background: Chronic kidney disease (CKD) characterized by tubular injury and fibrosis occurs in HIV infection treated with certain protease inhibitor (PI)-based antiretroviral therapies (ART). The pathophysiology is unclear.Methods: We hypothesized that fibrosis, mediated by platelet-derived transforming growth factor (TGF)-β1 and macrophage polarization to an inflammatory subtype underlies PI-associated CKD. We induced this in mice exposed to the PI ritonavir (RTV) in the absence of HIV, and intervened with low-dose inhaled carbon monoxide (CO), to activate erythroid 2- related factor (Nrf2)-associated anti-oxidant pathways. C57BL/6 mice, wild-type and deficient in platelet TGF-β1, were given RTV (10mg/kg) or vehicle daily for 8 weeks. Select groups were exposed to CO (250ppm) for 4 hours after RTV or vehicle injection. Renal pathology, fibrosis, and TGF-β1- and Nrf2-based signaling were examined by histology, immunofluorescence, and flow cytometry. Renal damage and dysfunction were assessed by KIM-1 and cystatin C ELISAs. Clinical correlations were sought among HIV-infected individuals.Findings: RTV induced glomerular and tubular injury, elevating urinary KIM-1. It enhanced TGF-β1-related signaling, accompanied by kidney fibrosis, macrophage polarization to an inflammatory phenotype, and renal dysfunction with cystatin C elevation. Mice with platelet TGF-β1 deletion were partially protected from these abnormalities. CO inhibited RTVinduced fibrosis and macrophage polarization in association with upregulation of Nrf2 and heme oxygenase-1 (HO-1). RTV use correlated with elevated cystatin C and HO-1 levels in HIV-infected individuals vs. controls and HIV-infected subjects receiving no therapy or non-PI-based regimens.Interpretation: Platelet TGF-β1 contributes to RTV-induced kidney fibrosis and dysfunction, which may be amenable to anti-oxidant-based interventions.Funding Statement: This work was supported by NIH grants R21 HL125044 (J.L. and J.A.), R01 HL123605 (J.A.), RO1 HL133801 and RO1 HL060234 (M.E.C.), COBRE grant GM114731, and funding from PHF (J.A.) and the Angelo Donghia Foundation (J.L.).Declaration of Interests: The spouse of M.E.C is a co-founder, shareholder and serves on the Scientific Advisory Board of Proterris, Inc. The remaining authors have no conflicts.Ethics Approval Statement: Animal studies were approved by the Institutional Animal Care and Use Committee of OMRF and WCMC. Patient samples were obtained through study approval by the Institutional Review Board of WCMC." @default.
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- W3149604645 date "2019-01-01" @default.
- W3149604645 modified "2023-10-14" @default.
- W3149604645 title "HIV Protease Inhibitor Ritonavir Induces Renal Fibrosis and Dysfunction: Role of Platelet-Derived TGF-β1 and Intervention via Anti-Oxidant Pathways" @default.
- W3149604645 doi "https://doi.org/10.2139/ssrn.3421589" @default.
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