Lysine Specific Demethylase‐1 Deficiency Accelerates the Development of Hypertension and Renal Damage During Long Term Sodium Intake

Abstract

AimsThis study aimed (1) to evaluate the timing of onset for changes in cardiovascular and renal (CVR) health during long term sodium loading in Lysine Specific Demethylase 1 (LSD1) deficiency and (2) to assess whether salt restriction can prevent these effects.MethodsLSD1‐HET and WT mice were randomized to high salt (HS), moderate salt (NS) or low salt (LS) and followed longitudinally for 12 months. BP, albumin/creatinine ratios (A/C), plasma aldosterone (PA) and renin activity (PRA) were assess monthly. At the end of study the renal arterial resistance index was measure by Doppler ultrasound.ResultsThe SBP (mmHg) increased progressively during the study, and reached significance on the 5thmonth for HS‐Het, 6thmonth for HS‐WT, 7thmonth for NS‐Het, 11thmonth for NS‐WT and 8thmonth for LS‐HET (132±3, 128±2, 125±3, 127±3 and 127±1 respectively, p<0.01 vs. baseline) but not for LS‐WT. Similar results were obtained for DBP (p<0.05), suggesting a volume mediated effect. The LS diet prevented the increase in BP only in WT mice.The A/C (μg/mg) was progressively increased in all groups, interestingly always preceding the BP change. Namely, A/C reached significance on the 3th,5th, 6th, 7th, 7th, 11thmonth for HS‐Het, HS‐WT, NS‐Het, NS‐WT, LS‐Het and LS‐WT (44±3,44±5, 35±2, 35±1, 38±3 and 40±2 respectively, p<0.05vs. baseline).PA and PRA were appropriately activated by dietary salt restriction and suppressed by aging.With the exception of LS‐WT (renal resistive index 0.69±0.01)., all groups developed renal resistanceConclusionsOur novel study showed that long‐term exposure to HS induced a progressive increase in BP in the WT, which was preceded by kidney damage. Interestingly in the LSD1‐Het, similar changes are initiated at an earlier age, suggesting that LSD1 is a critical component of mechanisms involved in CVR health.Importantly, the observed changes in BP and AC seem to be prevented by long‐term reductions in sodium intake in the WT. However, a stricter control of sodium intake was only able to delay and blunt the development of target‐organ damage and the hypertension in the LSD1‐Het model.Our study, performed in a clinically relevant animal model, suggest that LSD1 deficiency is a risk factor for cardiovascular and renal health, particularly during long‐term sodium loading, but also during moderately and severely restricted sodium diets.Support or Funding InformationFAPESP, CAPES and Amercian Heart AssociationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.