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MiR-144 mediates Nrf2 inhibition and alveolar epithelial dysfunction in HIV-1 transgenic rats.

American journal of physiology. Cell physiology (2019-05-16)
Abiodun T Kukoyi, Xian Fan, Bashar S Staitieh, Brooks M Hybertson, Bifeng Gao, Joe M McCord, David M Guidot

Chronic HIV infection causes redox stress and increases the risk of acute and chronic lung injury, even when individuals are adherent to antiretroviral therapy. HIV-1 transgene expression in rats inhibits nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates antioxidant defenses and alveolar epithelial cell (AEC) barrier function, but the mechanism is unknown. In this study, we present novel evidence that these pathological effects of HIV are mediated by microRNA-144 (miR-144). HIV-1 transgene expression in vivo increases the expression of miR-144 in the alveolar epithelium, and this can be replicated by direct exposure of naïve primary AECs to either Tat or gp120 ex vivo. Further, treating naïve primary AECs with a miR-144 mimic decreased the expression and activity of Nrf2 and inhibited their barrier formation. In contrast, treatment with a miR-144 antagomir increased the expression and activity of Nrf2 and improved barrier function in primary AECs isolated from HIV-1 transgenic rats. Importantly, either delivering the miR-144 antagomir intratracheally, or directly activating Nrf2 by dietary treatment with PB123, increased Nrf2 expression and barrier formation in HIV-1 transgenic rat AECs. This study provides new experimental evidence that HIV-induced inhibition of Nrf2 and consequent AEC barrier dysfunction are mediated via miR-144, and that these pathophysiological effects can be mitigated in vivo by either directly antagonizing miR-144 or activating Nrf2. Our findings suggest that targeting the inhibition of Nrf2 in individuals living with HIV could enhance their lung health and decrease the lung-specific morbidity and mortality that persists despite antiretroviral therapy.

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Anti-GAPDH antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
DL-Cysteine, technical grade