title: HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy.
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.
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Shabirul
authors.initials: S
authors.lastname: Haque
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Xiqian
authors.initials: X
authors.lastname: Lan
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Wen
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Rivka
authors.initials: R
authors.lastname: Lederman
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Amrita
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Attia
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Ramchandra P
authors.initials: RP
authors.lastname: Bongu
authors.affiliation: Jamia Millia Islamia, New Delhi, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Husain
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mikulak
authors.affiliation: Renal Academic Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, Tennessee.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Popik
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, New York.
authors.forename: Praveen N
authors.initials: PN
authors.lastname: Chander
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New York, New York. Electronic address: psinghal@nshs.edu.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D050199:Podocytes / Q000378:metabolism* / Q000821:virology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species