Abnormal activation of the mineralocorticoid receptor in the aldosterone-sensitive distal nephron contributes to fructose-induced salt-sensitive hypertension.

Fructose high-salt (FHS) diets increase blood pressure (BP). The mineralocorticoid receptor (MR) regulates Na+ reabsorption by the aldosterone-sensitive distal nephron (ASDN). The MR can be transactivated by glucocorticoids, including those locally produced by hydroxysteroid 11-beta dehydrogenase 1 (11β-HSD1). The epithelial sodium channel (ENaC) is a key transporter regulated by the MR. We hypothesized that fructose-induced salt-sensitive hypertension depends, in part, on abnormal activation of MRs in the ASDN, with consequent increases in ENaC expression. We found that aldosterone-upregulated genes in mice ASDN significantly overlapped with 74 genes upregulated by FHS in the rat kidney cortex (13/74; P ≤ 1 × 10-8), and that these 74 genes are prominently expressed in rat ASDN cells. In addition, the average z-score expression of mice aldosterone-upregulated genes is highly correlated with FHS compared with glucose high-salt (GHS) in the rat kidney cortex (Pearson correlation: r = 0.75, P ≤ 0.005). FHS and GHS suppressed serum aldosterone to similar levels; however, 11β-HSD1/11β-HSD2 ratio in the kidney cortex at both transcripts (Δ32 ± 13%; P ≤ 0.03; n = 6) and protein levels (Δ61 ± 27%; P ≤ 0.05; n = 6) was increased in FHS. FHS also increased BP by 23 ± 6 mmHg compared with GHS, and blocking MRs with eplerenone prevented this increase. In addition, inhibiting ENaC with amiloride significantly reduced BP in FHS from 148 ± 6 to 134 ± 5 mmHg (P ≤ 0.019). Compared with GHS, FHS increased total and cleaved αENaC protein by 89 ± 14% (P ≤ 0.03) and 47 ± 16% (P ≤ 0.01), respectively. FHS did not change β- or γ-subunit expression. These results suggest that fructose-induced salt-sensitive hypertension depends, in part, on abnormal Na+ retention by ENaC, resulting from the activation of MRs by glucocorticoids.NEW & NOTEWORTHY This study identifies abnormal mineralocorticoid receptor (MR) activation as a driver of fructose-induced salt-sensitive hypertension. Despite unchanged serum aldosterone levels, increased renal 11β-HSD1 suggests MR activation by glucocorticoids. The blood pressure increase caused by fructose and salt was reversed by MR blockade with eplerenone and ENaC inhibition with amiloride. These findings reveal a novel mechanism linking fructose consumption to abnormal distal nephron regulation, providing new insights into the pathogenesis of diet-induced hypertension.