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AIDS. 2020 Mar 11. doi: 10.1097/QAD.0000000000002516. [Epub ahead of print]

HIV protease inhibitor ritonavir induces renal fibrosis and dysfunction: role of platelet-derived TGF-β1 and intervention via anti-oxidant pathways.

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Division of Hematology and Medical Oncology.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA.
Department of Pathology, University of Oklahoma Health Sciences Center.
Division of Nephrology and Hypertension, Weill Cornell Medical College (WCMC), New York, NY, USA.



Chronic kidney disease (CKD) with tubular injury and fibrosis occurs in HIV infection treated with certain protease inhibitor (PI)-based antiretroviral therapies. The pathophysiology is unclear.


We hypothesized that fibrosis, mediated by platelet-derived transforming growth factor (TGF)-β1, underlies PI-associated CKD. We induced this in mice exposed to the PI ritonavir (RTV), and intervened with low-dose inhaled carbon monoxide (CO), activating erythroid 2-related factor (Nrf2)-associated anti-oxidant pathways.


C57BL/6 mice, wild-type and deficient in platelet TGF-β1, were given RTV (10 mg/kg) or vehicle daily for 8 weeks. Select groups were exposed to CO (250 ppm) 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.


RTV induced glomerular and tubular injury, elevating urinary KIM-1 (p = 0.004). It enhanced TGF-β1-related signaling, accompanied by kidney fibrosis, macrophage polarization to an inflammatory phenotype, and renal dysfunction with cystatin C elevation (p = 0.008). Mice with platelet TGF-β1 deletion were partially protected from these abnormalities. CO inhibited RTV-induced fibrosis and macrophage polarization in association with upregulation of Nrf2 and heme oxygenase-1 (HO-1). Clinically, HIV infection correlated with elevated cystatin C levels in untreated women (n = 17) vs. age-matched controls (n = 19; p = 0.014). RTV-treated HIV+ women had further increases in cystatin C (n = 20; p = 0.05), with parallel elevation of HO-1.


Platelet TGF-β1 contributes to RTV-induced kidney fibrosis and dysfunction, which may be amenable to anti-oxidant interventions.

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