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arXiv · 2507.02231

Downregulation of aquaporin 3 promotes hyperosmolarity-induced apoptosis of nucleus pulposus cells through PI3K/Akt/mTOR pathway suppression

Yuan Sang·Huiqing Zhao·Jiajun Wu·Ting Zhang·Wenbin Xu·Hui Yao·Kaihua Liu·Chang Liu·Junbin Zhang·Ping Li·Depeng Wu·Yichun Xu·Jianying Zhang·Gang Hou
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Abstract

Hyperosmolarity is a key contributor to nucleus pulposus cell (NPC) apoptosis during intervertebral disc degeneration (IVDD). Aquaporin 3 (AQP3), a membrane channel protein, regulates cellular osmotic balance by transporting water and osmolytes. Although AQP3 downregulation is associated with disc degeneration, its role in apoptosis under hyperosmotic conditions remains unclear. Here, we demonstrate that hyperosmolarity induces AQP3 depletion, suppresses the PI3K/AKT/mTOR signaling pathway, and promotes mitochondrial dysfunction and ROS accumulation in NPCs. Lentiviral overexpression of AQP3 restores this pathway, attenuates oxidative damage, and reduces apoptosis, preserving disc structure in IVDD rat models. In contrast, pharmacological inhibition of AQP3 exacerbates ECM catabolism and NP tissue loss. Our findings reveal that AQP3 deficiency under hyperosmolarity contributes to NPC apoptosis via suppression of PI3K/AKT/mTOR signaling, potentially creating a pathological cycle of disc degeneration. These results highlight AQP3 as a promising therapeutic target for IVDD.

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Yuan Sang, Huiqing Zhao, Jiajun Wu, Ting Zhang, Wenbin Xu, Hui Yao, Kaihua Liu, Chang Liu, Junbin Zhang, Ping Li, Depeng Wu, Yichun Xu, Jianying Zhang, Gang Hou. 2025-07-03. Downregulation of aquaporin 3 promotes hyperosmolarity-induced apoptosis of nucleus pulposus cells through PI3K/Akt/mTOR pathway suppression. https://arxiv.org/abs/2507.02231

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