Aquaporin 11 alleviates retinal Muller intracellular edema through water efflux in diabetic retinopathy

Retinal Muller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Muller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Muller glia in diabetic reti-nopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Muller 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 Muller 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 Muller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1 alpha-dependent and inde-pendent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Muller 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.

Automated summary

Retinal Muller glial dysfunction and intracellular edema in diabetic retinopathy (DR) are associated with down-regulation of Aquaporin 11 (AQP11). AQP11 overexpression alleviates intracellular edema, enhances glutamate metabolism, and reduces cell death. The down-regulation of AQP11 in DR is mediated by the miRNA-AQP11 axis, which is partially reversed by AQP11 overexpression. Targeting AQP11 regulation may provide a new therapeutic strategy for diabetic macular edema (DME).