Aquaporin 11 alleviates retinal Müller intracellular edema through water efflux in diabetic retinopathy. (January 2023)

• Record Type: Journal Article
• Authors: Zhang, Chaoyang; Luo, Dawei; Xie, Hai; Yang, Qian; Liu, Dandan; Tang, Lei; Zhang, Jingting; Li, Weiye; Tian, Haibin; Lu, Lixia; Sun, Xiaodong; Xu, Guo-Tong; Zhang, Jingfa
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: AQP11 aquaporin 11 -- BRB blood-retinal barrier -- BF bright field -- DR diabetic retinopathy -- DME diabetic macular edema -- ERM epiretinal membrane -- FSC-A forward scatter area -- GFAP glial fibrillary acidic protein -- GLAST glutamate-aspartate transporter -- GS glutamine synthetase -- HIF-1α hypoxia-inducible factor 1-alpha -- iMEM idiopathic macular epiretinal membrane -- INL inner nuclear layer -- LV lentivirus -- miRNA microRNA -- Na+-K+-ATPase sodium potassium-adenosine triphosphatase -- NPA asparagine–proline–alanine -- PDR proliferative diabetic retinopathy -- PlGF placental growth factor -- rMC-1 rat Müller cell line -- RPE retinal pigment epithelium -- RT-qPCR real-time quantitative PCR -- STZ streptozotocin -- TB toluidine blue -- UTR untranslated region -- VEGF vascular endothelial growth factor; Aquaporin 11 -- Diabetic retinopathy -- Diabetic macular edema -- Müller intracellular edema -- Na+-K+-ATPase -- MicroRNAs; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106559
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME. Graphical Abstract: AQP11 overexpression alleviates Müller intracellular edema. ga1