AT1a stimulation of tonicity‐responsive enhancer binding protein (TonEBP/NFAT5) translation through Annexin‐A2 may represent allostatic anticipation of increased tonicity

Abstract

Allostasis is idea that the body may anticipate homeostatic challenges and regulate cell and organ function in preparation. Angiotensin II (ANGII) is important for regulating sodium balance and as such increases tonicity in the renal medulla. The present study identifies a novel regulatory pathway whereby ANGII increases the translation of tonicity‐responsive enhancer binding protein (TonEBP/NFAT5) by activating nucleic acid binding of Annexin‐A2, which has several binding sites on NFAT5 mRNA and increases its translation. The activation of Annexin‐A2 was shown using heparin affinity chromatography and mass spectrometry in four‐week two‐kidney, one‐clip hypertension, and verified in two‐week ANGII infusion in rats. The addition of the AT1‐receptor blocker Losartan reduced the activation. Renal gene expression was studied using micro arrays, and identified NFAT5 targets as enriched. Western blot showed that NFAT5 protein was increased, while mRNA was not significantly regulated consistent with posttranscriptional regulation by Annexin‐A2. In conclusion, ANGII/AT1/Annexin‐A2‐mediated increase of the normally tonicity‐regulated NFAT5 in the kidney may be a way to ensure a more robust response to ANGII‐induced tonicity increase, and thus better protect homeostasis.Support or Funding InformationLars Hierta Foundation, Magnus Bergvall Foundation, Swedish Society for Medical Research.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.