Regulation of AQP4 Expression and Investigation of the Underlying Mechanisms by HIV-1 Tat Through the NMDAR/cAMP/PKA Signaling Pathway in Astrocytes
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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.
1. Spooner R, Ranasinghe S, Urasa S, Yoseph M, Koipapi S, Mukaetova-Ladinska EB, et al. HIV-Associated Neurocognitive Disorders: The First Longitudinal Follow-Up of a cART-Treated Cohort of Older People in Sub-Saharan Africa. Jaids-J Acq Imm Def. 2022;90(2):214-22.
2. Wei J, Hou J, Su B, Jiang T, Guo C, Wang W, et al. The Prevalence of Frascati-Criteria-Based HIV-Associated Neurocognitive Disorder (HAND) in HIV-Infected Adults: A Systematic Review and Meta-Analysis. Front Neurol. 2020;11:581346.
3. McDonnell J, Haddow L, Daskalopoulou M, Lampe F, Speakman A, Gilson R, et al. Minimal cognitive impairment in UK HIV-positive men who have sex with men: effect of case definitions and comparison with the general population and HIV-negative men. Jaids-J Acq Imm Def. 2014;67(2):120-7.
4. Rosenthal LS, Skolasky RL, Moxley RTT, Roosa HV, Selnes OA, Eschman A, et al. A novel computerized functional assessment for human immunodeficiency virus-associated neurocognitive disorder. J Neurovirol. 2013;19(5):432-41.
5. Cohen RA, Gullett JM, Porges EC, Woods AJ, Lamb DG, Bryant VE, et al. Heavy Alcohol Use and Age Effects on HIV-Associated Neurocognitive Function. Alcohol Clin Exp Res. 2019;43(1):147-57.
6. Ajasin D, Eugenin EA. HIV-1 Tat: Role in Bystander Toxicity. Front Cell Infect Mi. 2020;10:61.
7. Fulop T, Witkowski JM, Larbi A, Khalil A, Herbein G, Frost EH. Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer's disease? J Neurovirol. 2019;25(5):634-47.
8. Krogh KA, Wydeven N, Wickman K, Thayer SA. HIV-1 protein Tat produces biphasic changes in NMDA-evoked increases in intracellular Ca2+ concentration via activation of Src kinase and nitric oxide signaling pathways. J Neurochem. 2014;130(5):642-56.
9. Krogh KA, Lyddon E, Thayer SA. HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism. J Neurochem. 2015;132(3):354-66.
10. Kirchhoff F. Analysis of Functional NMDA Receptors in Astrocytes. Methods Mol Biol. 2017;1677:241-51.
11. Chen L, Zhang H, Xu R, Li W, Zhao H, Yang Y, et al. Interaction of aquaporin 4 and N-methyl-D-aspartate NMDA receptor 1 in traumatic brain injury of rats. Iran J Basic Med Sci. 2018;21(11):1148-54.
12. Dadgostar E, Rahimi S, Nikmanzar S, Nazemi S, Naderi Taheri M, Alibolandi Z, et al. Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target. Neurochem Res. 2022;47(4):860-71.
13. Dadgostar E, Tajiknia V, Shamsaki N, Naderi-Taheri M, Aschner M, Mirzaei H, et al. Aquaporin 4 and brain-related disorders: Insights into its apoptosis roles. Excli J. 2021;20:983-94.
14. Silva I, Silva J, Ferreira R, Trigo D. Glymphatic system, AQP4, and their implications in Alzheimer's disease. Neurol Res Pract. 2021;3(1):5.
15. St Hillaire C, Vargas D, Pardo CA, Gincel D, Mann J, Rothstein JD, et al. Aquaporin 4 is increased in association with human immunodeficiency virus dementia: implications for disease pathogenesis. J Neurovirol. 2005;11(6):535-43.
16. Xing HQ, Zhang Y, Izumo K, Arishima S, Kubota R, Ye X, et al. Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders. Neuropathology. 2017;37(1):25-34.
17. Hu Q, Chen X. MiR-27a-3p Enhances Endometrial Cancer Growth and EMT by Targeting LIFR and Activating the p38/MAPK Pathways. Iran J Biotechnol. 2025;23(3):e4008.
18. Wei Z, Ding H, Li H, Yin D, Cao J. Eicosapentaenoic Acid Modulates TGF-β1/Smad3/ILK Pathway to Attenuate Renal Fibrosis: A Biotechnological Approach. Iran J Biotechnol. 2025;23(2):e4098.
19. Bandera A, Taramasso L, Bozzi G, Muscatello A, Robinson JA, Burdo TH, et al. HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression? Front Aging Neurosci. 2019;11:187.
20. Wang Y, Liu M, Lu Q, Farrell M, Lappin JM, Shi J, et al. Global prevalence and burden of HIV-associated neurocognitive disorder: A meta-analysis. Neurology. 2020;95(19):e2610-21.
21. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-99.
22. Qi Y, Ailixire A, Gao Y, Li R, Li H. Current situation and prospect of HIV-associated neurocognitive disorder research in China: Epidemiology, research, diagnosis, and treatment status. Aids Rev. 2021;23(2):74-81.
23. Tice C, McDevitt J, Langford D. Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management? Front Cell Infect Mi. 2020;10:523379.
24. Dong H, Ye X, Zhong L, Xu J, Qiu J, Wang J, et al. Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis. Front Neurosci-Switz. 2019;13:44.
25. Wu X, Dong H, Ye X, Zhong L, Cao T, Xu Q, et al. HIV-1 Tat increases BAG3 via NF-kappaB signaling to induce autophagy during HIV-associated neurocognitive disorder. Cell Cycle. 2018;17(13):1614-23.
26. Saiyed ZM, Gandhi N, Agudelo M, Napuri J, Samikkannu T, Reddy PVB, et al. HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: implication for HIV-associated neurocognitive disorder (HAND). Neurochem Int. 2011;58(6):656-64.
27. Paris JJ, Chen X, Anderson J, Qrareya AN, Mahdi F, Du F, et al. In vivo proton magnetic resonance spectroscopy detection of metabolite abnormalities in aged Tat-transgenic mouse brain. Geroscience. 2021;43(4):1851-62.
28. Agrawal L, Louboutin J, Reyes BAS, Van Bockstaele EJ, Strayer DS. HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis. 2012;45(2):657-70.
29. Hu G, Liao K, Yang L, Pendyala G, Kook Y, Fox HS, et al. Tat-Mediated Induction of miRs-34a & -138 Promotes Astrocytic Activation via Downregulation of SIRT1: Implications for Aging in HAND. J Neuroimmune Pharm. 2017;12(3):420-32.
30. Chauhan A, Turchan J, Pocernich C, Bruce-Keller A, Roth S, Butterfield DA, et al. Intracellular human immunodeficiency virus Tat expression in astrocytes promotes astrocyte survival but induces potent neurotoxicity at distant sites via axonal transport. J Biol Chem. 2003;278(15):13512-9.
31. Bachani M, Sacktor N, McArthur JC, Nath A, Rumbaugh J. Detection of anti-tat antibodies in CSF of individuals with HIV-associated neurocognitive disorders. J Neurovirol. 2013;19(1):82-8.
32. Li W, Li G, Steiner J, Nath A. Role of Tat protein in HIV neuropathogenesis. Neurotox Res. 2009;16(3):205-20.
33. Green MV, Thayer SA. NMDARs Adapt to Neurotoxic HIV Protein Tat Downstream of a GluN2A-Ubiquitin Ligase Signaling Pathway. J Neurosci. 2016;36(50):12640-9.
34. Skowronska K, Obara-Michlewska M, Czarnecka A, Dabrowska K, Zielinska M, Albrecht J. Persistent Overexposure to N-Methyl-D-Aspartate (NMDA) Calcium-Dependently Downregulates Glutamine Synthetase, Aquaporin 4, and Kir4.1 Channel in Mouse Cortical Astrocytes. Neurotox Res. 2019;35(1):271-80.
35. Zhao F, Deng J, Xu X, Cao F, Lu K, Li D, et al. Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses. J Neuroinflamm. 2018;15(1):157.
36. Guo J, Mi X, Zhan R, Li M, Wei L, Sun J. Aquaporin 4 Silencing Aggravates Hydrocephalus Induced by Injection of Autologous Blood in Rats. Med Sci Monitor. 2018;24:4204-12.
37. Park H, Choi S, Kong M, Kang T. Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus. Front Cell Neurosci. 2019;13:236.
38. Cao J, Yao D, Li R, Guo X, Hao J, Xie M, et al. Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion. Neurosci Bull. 2022;38(2):181-99.
39. Verheggen ICM, Van Boxtel MPJ, Verhey FRJ, Jansen JFA, Backes WH. Interaction between blood-brain barrier and glymphatic system in solute clearance. Neurosci Biobehav R. 2018;90:26-33.
40. Vandebroek A, Yasui M. Regulation of AQP4 in the Central Nervous System. Int J Mol Sci. 2020;21(5)
41. Naganawa S, Taoka T. The Glymphatic System: A Review of the Challenges in Visualizing its Structure and Function with MR Imaging. Magn Reson Med Sci. 2022;21(1):182-94.
42. Mostafavi H, Khaksarian M, Joghataei MT, Hassanzadeh G, Soleimani M, Eftekhari S, et al. Fluoxetin upregulates connexin 43 expression in astrocyte. Basic Clin Neurosci. 2014;5(1):74-9.
43. Chen S, Yang J, Kong F, Ren J, Hao K, Li M, et al. Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema. P Natl Acad Sci Usa. 2014;111(36):13199-204.
44. Zhu M, Lu C, Xia C, Qiao Z, Zhu D. Simvastatin pretreatment protects cerebrum from neuronal injury by decreasing the expressions of phosphor-CaMK II and AQP4 in ischemic stroke rats. J Mol Neurosci. 2014;54(4):591-601.
45. Cumbay MG, Watts VJ. Galphaq potentiation of adenylate cyclase type 9 activity through a Ca2+/calmodulin-dependent pathway. Biochem Pharmacol. 2005;69(8):1247-56.
46. Marcelo KL, Means AR, York B. The Ca(2+)/Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft. Trends Endocrin Met. 2016;27(10):706-18.
47. Huang H, Liao D, Liang L, Song L, Zhao W. Genistein inhibits rotavirus replication and upregulates AQP4 expression in rotavirus-infected Caco-2 cells. Arch Virol. 2015;160(6):1421-33.
2. Wei J, Hou J, Su B, Jiang T, Guo C, Wang W, et al. The Prevalence of Frascati-Criteria-Based HIV-Associated Neurocognitive Disorder (HAND) in HIV-Infected Adults: A Systematic Review and Meta-Analysis. Front Neurol. 2020;11:581346.
3. McDonnell J, Haddow L, Daskalopoulou M, Lampe F, Speakman A, Gilson R, et al. Minimal cognitive impairment in UK HIV-positive men who have sex with men: effect of case definitions and comparison with the general population and HIV-negative men. Jaids-J Acq Imm Def. 2014;67(2):120-7.
4. Rosenthal LS, Skolasky RL, Moxley RTT, Roosa HV, Selnes OA, Eschman A, et al. A novel computerized functional assessment for human immunodeficiency virus-associated neurocognitive disorder. J Neurovirol. 2013;19(5):432-41.
5. Cohen RA, Gullett JM, Porges EC, Woods AJ, Lamb DG, Bryant VE, et al. Heavy Alcohol Use and Age Effects on HIV-Associated Neurocognitive Function. Alcohol Clin Exp Res. 2019;43(1):147-57.
6. Ajasin D, Eugenin EA. HIV-1 Tat: Role in Bystander Toxicity. Front Cell Infect Mi. 2020;10:61.
7. Fulop T, Witkowski JM, Larbi A, Khalil A, Herbein G, Frost EH. Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer's disease? J Neurovirol. 2019;25(5):634-47.
8. Krogh KA, Wydeven N, Wickman K, Thayer SA. HIV-1 protein Tat produces biphasic changes in NMDA-evoked increases in intracellular Ca2+ concentration via activation of Src kinase and nitric oxide signaling pathways. J Neurochem. 2014;130(5):642-56.
9. Krogh KA, Lyddon E, Thayer SA. HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism. J Neurochem. 2015;132(3):354-66.
10. Kirchhoff F. Analysis of Functional NMDA Receptors in Astrocytes. Methods Mol Biol. 2017;1677:241-51.
11. Chen L, Zhang H, Xu R, Li W, Zhao H, Yang Y, et al. Interaction of aquaporin 4 and N-methyl-D-aspartate NMDA receptor 1 in traumatic brain injury of rats. Iran J Basic Med Sci. 2018;21(11):1148-54.
12. Dadgostar E, Rahimi S, Nikmanzar S, Nazemi S, Naderi Taheri M, Alibolandi Z, et al. Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target. Neurochem Res. 2022;47(4):860-71.
13. Dadgostar E, Tajiknia V, Shamsaki N, Naderi-Taheri M, Aschner M, Mirzaei H, et al. Aquaporin 4 and brain-related disorders: Insights into its apoptosis roles. Excli J. 2021;20:983-94.
14. Silva I, Silva J, Ferreira R, Trigo D. Glymphatic system, AQP4, and their implications in Alzheimer's disease. Neurol Res Pract. 2021;3(1):5.
15. St Hillaire C, Vargas D, Pardo CA, Gincel D, Mann J, Rothstein JD, et al. Aquaporin 4 is increased in association with human immunodeficiency virus dementia: implications for disease pathogenesis. J Neurovirol. 2005;11(6):535-43.
16. Xing HQ, Zhang Y, Izumo K, Arishima S, Kubota R, Ye X, et al. Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders. Neuropathology. 2017;37(1):25-34.
17. Hu Q, Chen X. MiR-27a-3p Enhances Endometrial Cancer Growth and EMT by Targeting LIFR and Activating the p38/MAPK Pathways. Iran J Biotechnol. 2025;23(3):e4008.
18. Wei Z, Ding H, Li H, Yin D, Cao J. Eicosapentaenoic Acid Modulates TGF-β1/Smad3/ILK Pathway to Attenuate Renal Fibrosis: A Biotechnological Approach. Iran J Biotechnol. 2025;23(2):e4098.
19. Bandera A, Taramasso L, Bozzi G, Muscatello A, Robinson JA, Burdo TH, et al. HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression? Front Aging Neurosci. 2019;11:187.
20. Wang Y, Liu M, Lu Q, Farrell M, Lappin JM, Shi J, et al. Global prevalence and burden of HIV-associated neurocognitive disorder: A meta-analysis. Neurology. 2020;95(19):e2610-21.
21. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-99.
22. Qi Y, Ailixire A, Gao Y, Li R, Li H. Current situation and prospect of HIV-associated neurocognitive disorder research in China: Epidemiology, research, diagnosis, and treatment status. Aids Rev. 2021;23(2):74-81.
23. Tice C, McDevitt J, Langford D. Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management? Front Cell Infect Mi. 2020;10:523379.
24. Dong H, Ye X, Zhong L, Xu J, Qiu J, Wang J, et al. Role of FOXO3 Activated by HIV-1 Tat in HIV-Associated Neurocognitive Disorder Neuronal Apoptosis. Front Neurosci-Switz. 2019;13:44.
25. Wu X, Dong H, Ye X, Zhong L, Cao T, Xu Q, et al. HIV-1 Tat increases BAG3 via NF-kappaB signaling to induce autophagy during HIV-associated neurocognitive disorder. Cell Cycle. 2018;17(13):1614-23.
26. Saiyed ZM, Gandhi N, Agudelo M, Napuri J, Samikkannu T, Reddy PVB, et al. HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: implication for HIV-associated neurocognitive disorder (HAND). Neurochem Int. 2011;58(6):656-64.
27. Paris JJ, Chen X, Anderson J, Qrareya AN, Mahdi F, Du F, et al. In vivo proton magnetic resonance spectroscopy detection of metabolite abnormalities in aged Tat-transgenic mouse brain. Geroscience. 2021;43(4):1851-62.
28. Agrawal L, Louboutin J, Reyes BAS, Van Bockstaele EJ, Strayer DS. HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis. 2012;45(2):657-70.
29. Hu G, Liao K, Yang L, Pendyala G, Kook Y, Fox HS, et al. Tat-Mediated Induction of miRs-34a & -138 Promotes Astrocytic Activation via Downregulation of SIRT1: Implications for Aging in HAND. J Neuroimmune Pharm. 2017;12(3):420-32.
30. Chauhan A, Turchan J, Pocernich C, Bruce-Keller A, Roth S, Butterfield DA, et al. Intracellular human immunodeficiency virus Tat expression in astrocytes promotes astrocyte survival but induces potent neurotoxicity at distant sites via axonal transport. J Biol Chem. 2003;278(15):13512-9.
31. Bachani M, Sacktor N, McArthur JC, Nath A, Rumbaugh J. Detection of anti-tat antibodies in CSF of individuals with HIV-associated neurocognitive disorders. J Neurovirol. 2013;19(1):82-8.
32. Li W, Li G, Steiner J, Nath A. Role of Tat protein in HIV neuropathogenesis. Neurotox Res. 2009;16(3):205-20.
33. Green MV, Thayer SA. NMDARs Adapt to Neurotoxic HIV Protein Tat Downstream of a GluN2A-Ubiquitin Ligase Signaling Pathway. J Neurosci. 2016;36(50):12640-9.
34. Skowronska K, Obara-Michlewska M, Czarnecka A, Dabrowska K, Zielinska M, Albrecht J. Persistent Overexposure to N-Methyl-D-Aspartate (NMDA) Calcium-Dependently Downregulates Glutamine Synthetase, Aquaporin 4, and Kir4.1 Channel in Mouse Cortical Astrocytes. Neurotox Res. 2019;35(1):271-80.
35. Zhao F, Deng J, Xu X, Cao F, Lu K, Li D, et al. Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses. J Neuroinflamm. 2018;15(1):157.
36. Guo J, Mi X, Zhan R, Li M, Wei L, Sun J. Aquaporin 4 Silencing Aggravates Hydrocephalus Induced by Injection of Autologous Blood in Rats. Med Sci Monitor. 2018;24:4204-12.
37. Park H, Choi S, Kong M, Kang T. Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus. Front Cell Neurosci. 2019;13:236.
38. Cao J, Yao D, Li R, Guo X, Hao J, Xie M, et al. Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion. Neurosci Bull. 2022;38(2):181-99.
39. Verheggen ICM, Van Boxtel MPJ, Verhey FRJ, Jansen JFA, Backes WH. Interaction between blood-brain barrier and glymphatic system in solute clearance. Neurosci Biobehav R. 2018;90:26-33.
40. Vandebroek A, Yasui M. Regulation of AQP4 in the Central Nervous System. Int J Mol Sci. 2020;21(5)
41. Naganawa S, Taoka T. The Glymphatic System: A Review of the Challenges in Visualizing its Structure and Function with MR Imaging. Magn Reson Med Sci. 2022;21(1):182-94.
42. Mostafavi H, Khaksarian M, Joghataei MT, Hassanzadeh G, Soleimani M, Eftekhari S, et al. Fluoxetin upregulates connexin 43 expression in astrocyte. Basic Clin Neurosci. 2014;5(1):74-9.
43. Chen S, Yang J, Kong F, Ren J, Hao K, Li M, et al. Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema. P Natl Acad Sci Usa. 2014;111(36):13199-204.
44. Zhu M, Lu C, Xia C, Qiao Z, Zhu D. Simvastatin pretreatment protects cerebrum from neuronal injury by decreasing the expressions of phosphor-CaMK II and AQP4 in ischemic stroke rats. J Mol Neurosci. 2014;54(4):591-601.
45. Cumbay MG, Watts VJ. Galphaq potentiation of adenylate cyclase type 9 activity through a Ca2+/calmodulin-dependent pathway. Biochem Pharmacol. 2005;69(8):1247-56.
46. Marcelo KL, Means AR, York B. The Ca(2+)/Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft. Trends Endocrin Met. 2016;27(10):706-18.
47. Huang H, Liao D, Liang L, Song L, Zhao W. Genistein inhibits rotavirus replication and upregulates AQP4 expression in rotavirus-infected Caco-2 cells. Arch Virol. 2015;160(6):1421-33.
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How to Cite
1.
Li C, Duan R, Fu C. Regulation of AQP4 Expression and Investigation of the Underlying Mechanisms by HIV-1 Tat Through the NMDAR/cAMP/PKA Signaling Pathway in Astrocytes. Iran J Allergy Asthma Immunol. 2026;:1-15.
