We posit the existence of a paracrine/autocrine negative feedback loop, mediated by the mineralocorticoid receptor (MR), regulating aldosterone secretion. To assess this hypothesis we asked whether altering MR activity in zona glomerulosa (ZG) cells affects aldosterone production. To this end, we studied ex vivo ZG cells isolated from male Wistar rats fed chow containing either high (1.6% Na+ [HS]) or low (0.03% Na+ [LS]) amount of sodium. Western blot analyses demonstrated that MR was present in both the ZG and zona fasciculata/zona reticularis (ZF/ZR/ZR). In ZG cells isolated from rats on LS chow, MR activation by fludrocortisone produced a 20% and 60% reduction in aldosterone secretion basally and in response to angiotensin II (ANGII) stimulation, respectively. Corticosterone secretion was increased in these cells suggesting that aldosterone synthase activity was being reduced by fludrocortisone. In contrast, canrenoic acid, an MR antagonist, enhanced aldosterone production by up to 30% both basally and in response to ANGII. Similar responses were observed in ZG cells from rats fed HS. Modulating glucocorticoid receptor (GR) activity did not alter aldosterone production by ZG cells; however, altering GR activity did modify corticosterone production from ZF/ZR/ZR cells both basally and in response to adrenocorticotropic hormone (ACTH). Additionally, activating the MR in ZF/ZR/ZR cells strikingly reduced corticosterone secretion. In summary, these data support the hypothesis that negative ultra-short feedback loops regulate adrenal steroidogenesis. In the ZG, aldosterone secretion is regulated by the MR, but not the GR, an effect that appears to be secondary to a change in aldosterone synthase activity.
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 5 th and 6 th 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 4 th and 5 th 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.
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