Regulation of AQP4 Expression and Investigation of the Underlying Mechanisms by HIV-1 Tat Through the NMDAR/cAMP/PKA Signaling Pathway in Astrocytes.

Authors

Chuo Li, Ran Duan, Congcong Fu

Published in

Iranian journal of allergy, asthma, and immunology. Volume 25. Issue 4. Pages 602-616. Jun 03, 2026. Epub Jun 03, 2026.

Abstract

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remains a major neurological complication in people living with HIV despite effective antiretroviral therapy. Neurotoxicity caused by viral proteins, particularly the HIV-1 transactivator of transcription (Tat), contributes significantly to HAND. Although N-methyl-D-aspartate receptors (NMDARs) in astrocytes are known to regulate aquaporin-4 (AQP4) the mechanisms by which Tat influences NMDAR signaling and AQP4 expression remain unclear. This study investigated how HIV-1 Tat regulates AQP4 expression in astrocytes through the NMDAR/CaMKII/AC/cAMP/PKA signaling pathway and how secondary Ca2+ dynamics modulate this process. Astrocytic Ca2+ influx was measured using the Fluo-3 AM probe. Western blotting quantified AQP4, NR1, NR2A/B, CaMKII, p-CaMKII, PKA, and PKG expression. Real-time quantitative polymerase chain reaction (RT-qPCR) assessed mRNA levels of AQP4 and NMDAR-related genes. Enzyme-linked immunosorbent assay (ELISA) evaluated nitric oxide synthase activity, adenylate cyclase activity, and intracellular cAMP levels. Pharmacologic inhibitors-MK-801 (NMDAR blocker), H89 (PKA inhibitor), and KT5823 (protein kinase G [PKG] inhibitor)-were applied to investigate pathway interactions. HIV-1 Tat induced robust activation of NMDAR, resulting in increased Ca2+ influx and sequential activation of the CaMKII/AC/cAMP/PKA pathway, ultimately elevating AQP4. After prolonged Tat exposure (approximately 36 hours), a secondary surge in Ca2+ activated PKG, which acts as a protective negative feedback mechanism to inhibit excessive NMDAR activity, thereby stabilizing Ca2+ influx and preventing abnormal overexpression of AQP4. Cotreatment with MK-801, H89, or KT5823 suppressed Tat-induced Ca2+ influx and attenuated AQP4 upregulation, although persistent Tat exposure gradually restored Ca2+ elevations through compensatory mechanisms. HIV-1 Tat dynamically regulates AQP4 expression in astrocytes via the NMDAR/CaMKII/AC/cAMP/PKA pathway, with PKG-mediated feedback contributing to later stabilization. These findings highlight AQP4 as a potential therapeutic target for HAND.

PMID:
42437320
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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