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

OBJECTIVE: 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.

DESIGN: 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.

METHODS: 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.

RESULTS: 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.

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