Abstract P117: Lysine Specific Demethylase-1 Deficiency Accelerates the Development of Renal Damage and Hypertension During Long Term Exposure to Sodium
Long term exposure to salt is a demonstrated risk factor for hypertension (HT), as well as cardiovascular and renal (CVR) outcomes. We recently proposed a novel contributor to the etiology of salt-mediated HT: the Lysine Specific Demethylase-1 (LSD1). We showed that LSD1 deficiency (in mice) and LSD1 gene variants (in humans) associate - in response to short term (one week) of sodium loading - with dysregulated renal sodium handling, volume expansion and HT, and RAAS dysfunction. However, the timeline and severity of these changes during long term exposure to sodium, and the protective effects of sodium restriction in LSD1 deficient states have yet to be determined. This study aimed (1) to evaluate the timing of onset for changes in CVR health during long term sodium loading in LSD1 deficient mice and (2) to assess whether a low salt (LS) diet can prevent these effects. LSD1 heterozygous (HET) and WT mice were randomized to high salt (HS) or LS and followed longitudinally for 6 months. BP, plasma aldosterone (Aldo) and albumin/creatinine ratios (A/C) were assessed monthly.
The SBP (mm Hg) increased progressively during the study, and reached significance on the 5th and 6th month for HS-HET and HS-WT (141±4 and 134±3, respectively, both p<0.05 vs. baseline) but not for LS-HET and LS-WT (128±6 and 120±6, respectively). The SBP effects were driven by a significant interaction between genotype and age (p<0.05). Similar results were obtained for DBP (p<0.05), suggesting a volume mediated effect. HS plasma Aldo was appropriately suppressed.
The A/C (μg/mg) was progressively increased in both HS groups, one month prior to the BP change. Namely, A/C reached significance on the 4th and 5th month for HS-HET and HS-WT (46±4 and 48±9, respectively, both p<0.05 vs. baseline). The LS diet prevented these changes in both genotypes.
Our novel study shows that long term exposure to HS induces kidney damage followed by BP increase, and that these changes are initiated earlier in the LSD1 HET, suggesting LSD1 as a critical component of mechanisms involved in CVR health. Moreover, long term sodium restriction prevented the development of both target organ damage and HT in this model, suggesting that this dietary intervention may be particularly efficient in human carriers of LSD1 gene variants.
Author Disclosures: I.A. Katayama Rangel: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; Capes (#BEX 6752-14-4). C. Chong: None. G.H. Williams: None. L.H. Pojoga: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; American Heart Association Grant-In-Aid (14GRNT20500000).
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
- © 2015 by American Heart Association, Inc.