HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy

Shabirul Haque, Xiqian Lan, Hongxiu Wen, Rivka Lederman, Amrita Chawla, Mohamed Attia, Ramchandra P Bongu, Mohammad Husain, Joanna Mikulak, Moin A Saleem, Waldemar Popik, Ashwani Malhotra, Praveen N Chander, Pravin C Singhal

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Abstract

Dysregulated growth and loss of podocytes are important features of HIV-associated nephropathy. Recently, HIV was reported to induce a new type of programed cell death, pyroptosis, in T lymphocytes through induction of Nod-like receptor protein 3 (NLRP3) inflammasome complexes. We evaluated the role of HIV in podocyte NLRP3 inflammasome formation both in vivo and in vitro. Renal cortical sections of HIV-transgenic mice (Tg26) displayed increased expression of NLRP3, ASC (a CARD protein), caspase-1, and IL-1β proteins, confirming NLRP3 inflammasome complex formation in podocytes of Tg26 mice. Renal tissues of Tg26 mice also displayed enhanced mRNA levels and protein expressions of inflammasome markers (NLRP3, ASC, and caspase-1, and IL-1β). Serum of Tg26 mice also showed elevated concentrations of IL-1β cytokine compared with FVBN mice. HIV induced pyroptosis in a dose- and time-dependent manner within podocytes, a phenotype of inflammasome activation. Caspase-1 inhibitor not only attenuated podocyte expression of caspase-1 and IL-1β but also provided protection against pyroptosis, suggesting that HIV-induced podocyte injury was mediated by caspase-1 activation. Interestingly, HIV-induced podocyte pyroptosis could be partially inhibited by Tempol (a superoxide dismutase-mimetic agent) and by glyburide (an inhibitor of potassium efflux). These findings suggest that generation of reactive oxygen species and potassium efflux contribute to HIV-induced pyroptosis and NLRP3 inflammasome activation in podocytes.

Original languageEnglish
JournalAmerican Journal of Pathology
DOIs
Publication statusPublished - 10 Dec 2015

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    Haque, S., Lan, X., Wen, H., Lederman, R., Chawla, A., Attia, M., Bongu, R. P., Husain, M., Mikulak, J., Saleem, M. A., Popik, W., Malhotra, A., Chander, P. N., & Singhal, P. C. (2015). HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy. American Journal of Pathology. https://doi.org/10.1016/j.ajpath.2015.10.002