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:We examined Na-dependent changes in gene expression in the renal papilla and heart ventricle of rats. Animals were conditioned with control or low-Na diets for 1 week. RNA isolated from kidneys or hearts was analyzed by RNAseq. In the renal papilla, notable genes upregulated in response to low dietary Na included alpha, betta, and gamma subunits of ENaC, alpha and beta subunits of the Na/K-ATPase, and the transcription factor Zbtb16. Increases in mRNA for the ENaC were confirmed using qPCR and were strongly dependent on location within the kidney with papilla > outer medulla > cortex. Differences in ENaC protein expression exhibited a similar dependence on location. The effects of dietary Na+ on ENaC expression, as well as that of Zbtb16, in the papillae were not mimicked by treatment with aldosterone, indicating that other factors contribute to the adaptation to Na+ deprivation. In the heart, a smaller number of genes were affected by dietary Na+. Effects clearly related to Na+ balance included downregulation of transcripts for the natriuretic peptides ANP and BNP. Enrichment analyses indicated that low dietary Na led to upregulation of many Gene Ontology (GO) gene sets related to growth and development in the kidney samples, but downregulation of such gene sets in the heart. Our results illustrate the profound site- and tissue-specific effects of changes in dietary Na+ on renal and cardiac gene expression and regulation of salt balance.