Research reveals that hypernatremia characterized by excess sodium linked to dehydration, induced by insufficient fluid intake, diarrhea, kidney failure or even the use of diuretics, increases the production of NFAT5 factor and nitric oxide. (NO) in microglia. A compound, minocycline, however, helps to attenuate this excessive response, which is harmful to microglia.
Microglia are a group of immune cells in the brain that protect neuronal function from possible threats. When elevated extracellular sodium levels occur, the brain is subjected to hyperosmotic stress, and the microglial response may become exaggerated, leading to potentially harmful effects.
Counteracting the microglia response to hypernatremia
The study explores the effects of hyperosmotic stress on microglial cells and focuses on the role of NFAT5, a transcription factor known to regulate cellular responses to osmotic stress. While the role of NFAT5 is well documented in other cell types, its function in microglia remains poorly understood. The researchers therefore looked at whether NFAT5 influences the expression of NOS2, an enzyme involved in the production of NO, under these hyperosmotic conditions.
The team therefore subjected microglial cells to hyperosmotic stress by increasing extracellular sodium concentrations by 20 and 40 mM above normal levels, measured changes in NFAT5 expression, NOS2 expression and of NO production. One pathway has been identified as major in this process, Na+/Ca2+, NCX. This work reveals that:
- acute and chronic hyperosmotic stress significantly increases the expression of the factor NFAT5 in microglial cells;
- This upregulation of NFAT5 is associated with increased expression of NOS2 and an increase in NO production, indicating that NFAT5 plays a crucial role in modulating microglial responses to hyperosmotic stress;
- NCX is also involved in this process;
- In summary, hyperosmotic stress triggers the efflux of Ca2+ via NCXwhich contributes to elevated NOS2 expression and NO production;
- this process appears to occur independently of NFAT5, suggesting that several activation pathways are involved in this noxious microglial response to hyperosmotic stress.
Secondly, the researchers evaluated the therapeutic effects of minocyclinean anti-inflammatory drug, on microglial responses to hyperosmotic stress and, precisely on the pathway involved, Na+/Ca2+, NCX, in this process. These experiments reveal that:
- minocycline effectively inhibits NOS2 expression and hyperosmotic stress-induced NO production, confirming its therapeutic potential to manage conditions associated with high sodium levels;
- however, this inhibitory effect of minocycline appears to be independent of NFAT5, again suggesting other underlying mechanisms.
These results will need to be validated by preclinical studies, but this initial in vitro work already identifies new targets making it possible to limit the impact of hyperosmotic stress on microglial function and the brain. With the prospect also, new therapeutic agents.
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