Project description:Inflammation and infection can trigger local tissue Na+-accumulation. This Na+-rich environment boosts pro-inflammatory activation of monocyte/macrophage-like cells (MΦ) and their antimicrobial activity. Enhanced Na+-driven MΦ-function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments NO production and contributes to increased autophagy. However, the mechanism of Na+-sensing in MΦ remained unclear. High extracellular Na+ levels (HS) trigger a substantial Na+-influx and Ca2+ loss. Here, we show that the Na+/ Ca2+-exchanger 1 (NCX1/ solute carrier family 8 member A1 (SLC8A1)) plays a critical role in HS-triggered Na+-influx, concomitant Ca2+ efflux and subsequent NFAT5 accumulation. Moreover, interfering with NCX1-activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.
Project description:The purpose of this study was to investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na+-HCO3- cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury. An NBCe1 (Slc4a4 gene) cardiac conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wild-type (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in cardiac gene expression were determined by RNA Seq analysis. Response to in vivo I/R injury was analyzed after 30 minutes occlusion of the left anterior descending artery followed by 3 hours of reperfusion. Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections. These studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against I/R injury in vivo.
Project description:To investigate the claudin-7 function in vivo, we generated a claudin-7 knockout mouse model by gene targeting through homologous recombination. In this study, we report that Cln7-/- pups show Na+, Cl-, and K+ wasting and chronic dehydration phenotypes. The dramatic increase of aldosterone synthase mRNA level suggests that these mice suffer from mishandling of NaCl and fluid in the distal nephrons. Deletion of claudin-7 invokes several compensatory changes, such as increased renin, serum-glucocorticoid-induced kinase 1 (SGK1), epithelial Na+ channel (ENaCα), Na+-Cl- cotransporter (NCC), as well as aquaporin (AQP) 2 mRNA levels, demonstrating the cross talks between paracellular and transcellular ion transport pathways.