Yak OXGR1 promotes fibroblast proliferation via the PI3K/AKT pathways

Abstract

Oxoglutarate receptor 1 (OXGR1), as one of the intermediates in G protein‐coupled receptors (GPCRs), plays a crucial role in the citric acid cycle receptor of α‐ketoglutarate and metabolism. GPCR can control the cell proliferation by regulating the downstream signaling of G protein signaling pathways. The PI3K/AKT pathway transmits the downstream signals of GPCRs and receptor tyrosine kinases. However, the specific role of OXGR1 promoting cell proliferation and differentiation are still unknown. In current study, the over‐expression vector and knockdown sequence of yak OXGR1 were transfected into yak fibroblasts, and the effects were detected by a series of assays. The results revealed that OXGR1 expression in yak lung parenchyma tissue was significantly higher than that of other tissues. In yak fibroblasts, the upregulated expression of OXGR1 resulted in activating the PIK3CG (downstream signal) of the PI3K/AKT1 pathway that can upregulated the expression of proliferation genes ( CDK1, PCNA, and CyclinD1) and promote cell proliferation. Conversely, the downregulated expression of OXGR1 inhibited cell proliferation via PI3K/AKT1 pathway. Cell cycle and cell proliferation assays demonstrated that over‐expression of OXGR1 can enhanced the DNA synthesis and promoted yak fibroblasts proliferation. While the conversely, knockdown of OXGR1 can decreased DNA synthesis and inhibited cell proliferation. These results illustrated that changes of OXGR1 expression can trigger the fibroblasts proliferation via PI3K/AKT signaling pathway, which indicating that OXGR1 is a novel regulator for cell proliferation and differentiation. Furthermore, these results provide evidence supporting the functional role of GPCRs‐PI3K‐AKT1 and OXGR1 in cell proliferation.

Transcriptomics reveals age-related changes in ion transport–related factors in yak lungs

“…The PI3K-Akt pathway may prevent cell apoptosis in the neonatal yak lungs, promoting alveolar and airway cell proliferation and development, thereby influencing lung structure formation and development. The immunoregulatory function of the PI3K-AKT pathway is mainly mediated through various receptors, including insulin receptors, pathogen-associated molecular pattern receptors, cytokine receptors, and hormones, participating in macrophage response regulation ( 19 ). In adult yak lungs, the PI3K-Akt pathway may be involved in responses to external environmental pressures, such as oxygen concentration changes or other environmental stimuli, to maintain lung adaptability and stability.…”

Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response

“…Additionally, this phenomenon could be related to an increased level of pFoxO1 in αKG-moDCs. Namely, exogenous αKG may activate PI3K/Akt signalling via αKG-receptor GPR99 (OXGR1) 101 , and this pathway leads to increased cytosolic FoxO1, which was found to directly induce autophagy in cancer cell lines by binding to Atg7 44 . LPS was shown to reduce autophagy in moDCs under normoxic conditions 92 , unlike IFN-γ which induces autophagy 102 , which can explain the lack of significant change in the autophagy flux in LPS/IFN-γ-matured vs immature moDCs.…”

Activation of 2‐oxoglutarate receptor 1 (OXGR1) by α‐ketoglutarate (αKG) does not detectably stimulate Pendrin‐mediated anion exchange in Xenopus oocytes

“…OXGR1 is also one of the multiple GPCRs that can serve as a cellular entry pathway for several strains of influenza virus (Orr‐Burks et al, 2021 ), and is essential for optimal viral proliferation. OXGR1 is expressed in Glp‐1‐positive enteroendocrine cells (Roberts et al, 2019 ) and has been variously been implicated in respiratory epithelial mucin production (Bankova et al, 2016 ), hypertrophic cardiomyopathy (Omede et al, 2016 ), fibroblast proliferation (Wang et al, 2019 ), and axon growth but not guidance (Cherif et al, 2018 ). An OXGR1 variant of unknown significance has also been linked to early ischemic stroke in families with a history of stroke (Ilinca et al, 2020 ).…”