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Deficiency of lysophosphatidic acid receptor 3 decreases the erythropoietin production in hypoxic mouse kidney

ABSTRACT: As a simple lipid mediator, Lysophosphatidic acid (LPA) exerts its function by binding to 6 GPCRs (LPAR1-6) on the cell membrane. Among the 6 LPA receptors, LPAR3 is highly expressed in mouse kidney, where it has only been found to play a harmful role in kidney ischemia-reperfusion injury and diabetic nephropathy. Our previous research and other researchers found the correlation between the ATX-LPA-LPAR axis and hypoxia-related biological processes. The kidney is one of the most susceptible organs to hypoxia. It is therefore interesting to identify the function of LPAR3 in hypoxic mice kidneys. In this study, the wild-type (WT) and Lpar3-/- mice were put into a normobaric hypoxic installation and RNA sequencing analysis showed that Lpar3-/- mice showed a significant decrease in hypoxia-induced EPO expression in the kidney compared with WT mice. The impaired EPO gene expression resulted in reduced plasma EPO levels and lower hematocrit and hemoglobin levels. The KEGG enrichment analysis revealed the reduced accumulation of HIF-2α caused by LPAR3 deficiency may be the reason for insufficient hypoxic renal EPO production. In in-vitro hypoxic cell models (Hep3B cells and HK2 cells), targeting LPAR3 can also regulate HIF-2α and EPO expression. KEGG analysis revealed that the PI3K/Akt signaling pathway was involved in the regulation of LPAR3 on HIF-2α-EPO, which was validated at the tissue level and cell level. Taken together, this study demonstrates that the murine renal LPAR3 promotes HIF-2α accumulation to maintain renal EPO production by activating the downstream PI3K/Akt pathway, ensuring the generation of red blood cells in mice and plays an important role in the body's adaptation to hypoxia.

ORGANISM(S): Mus musculus

PROVIDER: GSE264135 | GEO | 2024/11/27

REPOSITORIES: GEO

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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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Deficiency of lysophosphatidic acid receptor 3 decreases the erythropoietin production in hypoxic mouse kidney

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