Arg2, also known as arginase 2, is a key hydrolase in the urea cycle, hydrolyzing L-arginine to urea and L-ornithine. It is involved in multiple biological pathways and has significant importance in various physiological and disease-related processes. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in studying its function [4].

In non-alcoholic steatohepatitis (NASH), conditional knockout of Spp1 in myeloid cells worsened NASH, while conditional knockin of Spp1 in myeloid cells or hepatic macrophages conferred protection. This protective effect was mediated by the induction of ARG2, which enhanced fatty acid oxidation in hepatocytes. Specifically, enhanced production of oncostatin-M in macrophages from Spp1KI Mye mice activated STAT3 signaling, upregulating ARG2 [1]. In adenomyosis, silencing ARG2 in endometrial cells led to decreased cell viability, G0/G1 cell cycle arrest, apoptosis, and mitochondrial dysfunction. In vivo study in a mouse model of adenomyosis also demonstrated that siARG2 treatment reversed epithelial-to-mesenchymal transition and modulated inflammatory cytokines [2]. In osteoarthritis, lactate up-regulated ARG2 expression in fibroblast-like synoviocytes, promoting cellular senescence, and this effect could be attenuated by siRNA-Arg2 [3]. In contrast-induced acute kidney injury (CI-AKI), ARG2 accumulated in the tubules of CI-AKI mice. ARG2 knockout mice showed ameliorated kidney dysfunction, tubular injury, decreased nitrosative stress and apoptosis [5].

In conclusion, Arg2 plays essential roles in multiple biological processes, including fatty acid oxidation, cell cycle regulation, apoptosis, cellular senescence, and nitrosative stress. KO/CKO mouse models have significantly contributed to understanding Arg2's function in diseases like NASH, adenomyosis, osteoarthritis, and CI-AKI, providing potential therapeutic targets for these conditions.

References:

1. Han, Hui, Ge, Xiaodong, Komakula, Sai Santosh Babu, Guzman, Grace, Nieto, Natalia. 2023. Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis. In Gastroenterology, 165, 201-217. doi:10.1053/j.gastro.2023.03.228. https://pubmed.ncbi.nlm.nih.gov/37028770/

2. Xu, Yaping, Shao, Lin, Zhou, Zhan, Wanyan, Wenya, Yuan, Yinping. 2024. ARG2 knockdown promotes G0/G1 cell cycle arrest and mitochondrial dysfunction in adenomyosis via regulation NF-κB and Wnt/Β-catenin signaling cascades. In International immunopharmacology, 140, 112817. doi:10.1016/j.intimp.2024.112817. https://pubmed.ncbi.nlm.nih.gov/39116499/

3. Huang, Yifan, Yue, Songkai, Yan, Zhihua, Dong, Yonghui, Zheng, Jia. 2024. Lactate-upregulated ARG2 expression induces cellular senescence in fibroblast-like synoviocytes of osteoarthritis via activating the mTOR/S6K1 signaling pathway. In International immunopharmacology, 142, 113071. doi:10.1016/j.intimp.2024.113071. https://pubmed.ncbi.nlm.nih.gov/39236462/

4. Niu, Fanglin, Yu, Yi, Li, Zhuozhuo, Qian, Lu, Xiong, Yuyan. 2022. Arginase: An emerging and promising therapeutic target for cancer treatment. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 149, 112840. doi:10.1016/j.biopha.2022.112840. https://pubmed.ncbi.nlm.nih.gov/35316752/

5. Zhou, Ling-Yun, Liu, Kun, Yin, Wen-Jun, Wu, Yi-Feng, Zuo, Xiao-Cong. 2023. Arginase2 mediates contrast-induced acute kidney injury via facilitating nitrosative stress in tubular cells. In Redox biology, 67, 102929. doi:10.1016/j.redox.2023.102929. https://pubmed.ncbi.nlm.nih.gov/37856999/