Voltage-gated proton channels (VSOP/Hv1) reportedly promote reactive oxygen species (ROS) production in several immune cell types. However, we recently reported that primary microglia from VSOP/Hv1-deficient mice show higher ROS production than those from WT mice. Microglia may show a distinct activation status between WT and VSOP/Hv1-deficient cells, leading to a distinct level of ROS production between them. This is unlikely, however, because ROS production in VSOP/Hv1-deficient microglia remained higher than in WT microglia when the cells were exposed to LPS. Further, this increase in ROS production in VSOP/Hv1-deficient cells was not observed in macrophages, which suggests microglia have a unique mechanism of VSOP/Hv1-dependent ROS regulation. The mechanism underlying this unconventional ROS regulation by VSOP/Hv1 in microglia is discussed.

Voltage-gated proton channels (Hv1/VSOP), encoded by Hvcn1, are important regulator of reactive oxygen species (ROS) production in many types of immune cells. While in vitro studies indicate that Hv1/VSOP regulates ROS production by maintaining pH homeostasis, there are few studies investigating the functional importance of Hv1/VSOP in vivo. In the present study, we first show that Hv1/VSOP is functionally expressed in liver resident macrophage, Kupffer cells, regulating the hepatic oxidative stress in vivo. Our immunocytochemistry and electrophysiology data showed that Hvcn1 is specifically expressed in Kupffer cells, but not in hepatocytes. Furthermore, Hvcn1-deficiency drastically altered the hepatic oxidative stress. The Hvcn1-deficient mice showed high blood glucose and serum insulin but normal insulin sensitivity, indicating that these phenotypes were not linked to insulin resistance. Transcriptome analysis indicated that the gene expression of glycogen phosphorylase (Pygl) and Glucose-6-phosphatase, catalytic subunit (G6pc) were upregulated in Hvcn1-deficient liver tissues, and quantitative PCR confirmed the result for Pygl. Furthermore, we observed higher amount of glucose-6-phosphate, a key sugar intermediate for glucose in Hvcn1-deficient liver than WT, suggesting that glucose production in liver is accelerated in Hvcn1-deficient mice. The present study sheds light on the functional importance of Kupffer cells in hepatic oxidative stress and its potential relationship with glucose metabolism. K E Y W O R D S blood glucose, Kupffer cell, voltage-gated proton channels 2 | KAWAI et Al.