Aqp9, an aquaglyceroporin, is a small membrane-spanning protein. It is permeable to water, hydrogen peroxide (H2O2), glycerol, and even larger solutes like lactate [2,3,4]. Aqp9 is involved in multiple biological processes, such as hepatocyte H2O2 homeostasis, glucose metabolism, and macrophage polarization. It is associated with pathways like the LPA-hippo pathway, and its functions are crucial in maintaining normal physiological states [1,2]. Genetic models, especially knockout (KO) mouse models, have been instrumental in studying Aqp9's functions.

In a CD mouse model, specific inhibition of Aqp9 significantly enhanced the response to anti-TNF therapy. Blockade of Aqp9 in macrophages decreased their inflamed functions and cytokine expression, revealing its role in the LPA-hippo pathway activation and cytokine production in Crohn's disease [1]. Aqp9 -/- mice showed impaired liver regeneration, increased hepatic H2O2 concentration, and abnormal glucose metabolism, indicating its importance in liver regeneration [2]. In a tumor allograft mouse model, Aqp9 knockout mice were more resistant to tumor cell growth with suppressed M2-like polarization in tumor tissue, suggesting Aqp9's role in promoting tumor progression through lactate-induced macrophage polarization [3].

In conclusion, Aqp9 plays essential roles in biological processes like liver regeneration, macrophage polarization, and disease-related cytokine regulation. The use of Aqp9 KO mouse models has provided valuable insights into its functions in diseases such as Crohn's disease, liver injury, and colon cancer, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Yu, Minhao, Shi, Yuan, Gao, Yuan, Cao, Zhijun, Zhong, Ming. 2024. Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway. In Pharmacological research, 203, 107172. doi:10.1016/j.phrs.2024.107172. https://pubmed.ncbi.nlm.nih.gov/38583685/

2. Zhang, Bo, Lv, Dongyue, Chen, Yang, Chen, Siqing, Ma, Tonghui. 2022. Aquaporin-9 facilitates liver regeneration following hepatectomy. In Redox biology, 50, 102246. doi:10.1016/j.redox.2022.102246. https://pubmed.ncbi.nlm.nih.gov/35086002/

3. Shi, Yundi, Yasui, Masato, Hara-Chikuma, Mariko. 2022. AQP9 transports lactate in tumor-associated macrophages to stimulate an M2-like polarization that promotes colon cancer progression. In Biochemistry and biophysics reports, 31, 101317. doi:10.1016/j.bbrep.2022.101317. https://pubmed.ncbi.nlm.nih.gov/35967760/

4. Verkman, A S, Mitra, A K. . Structure and function of aquaporin water channels. In American journal of physiology. Renal physiology, 278, F13-28. doi:. https://pubmed.ncbi.nlm.nih.gov/10644652/