title: Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways.
abstract: Although salt is a major environmental factor in the development of hypertension, the degree of salt sensitivity varies widely among individuals. The mechanisms responsible for this variation remain to be elucidated. Recent studies have revealed the involvement of two important signaling pathways in renal tubules that play key roles in electrolyte balance and the maintenance of normal blood pressure: the β2-adrenergic stimulant-glucocorticoid receptor (GR)-with-no-lysine kinase (WNK)4-Na(+)-Cl(-) cotransporter pathway, which is active in distal convoluted tubule (DCT)1, and the Ras-related C3 botulinum toxin substrate (Rac)1-mineralocorticoid receptor (MR) pathway, which is active in DCT2, connecting tubules, and collecting ducts. β2-Adrenergic stimulation due to increased renal sympathetic activity in obesity- and salt-induced hypertension suppresses histone deacetylase 8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter. This results in the suppression of WNK4 transcription followed by the activation of Na(+)-Cl(-) cotransporters in the DCT and elevated Na(+) retention and blood pressure upon salt loading. Rac1 activates MRs, even in the absence of ligand binding, with this activity increased in the presence of ligand. In salt-sensitive animals, Rac1 activation due to salt loading activates MRs in DCT2, connecting tubules, and collecting ducts. Thus, GRs and MRs are independently involved in two pathways responsible for renal Na(+) handling and salt-sensitive hypertension. These findings suggest novel therapeutic targets and may lead to the development of diagnostic tools to determine salt sensitivity in hypertensive patients.
authors.affiliation: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nishimoto
authors.affiliation: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan Toshiro.FUJITA@rcast.u-tokyo.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007684:Kidney Tubules / Q000294:innervation / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D049992:Sodium Chloride Symporters / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000009:adverse effects* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000503:physiopathology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D053503:Epithelial Sodium Channels; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D049992:Sodium Chloride Symporters; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein
keywords: Ras-related C3 botulinum toxin substrate 1; glucocorticoid receptor; mineralocorticoid receptor; salt-sensitive hypertension; sympathetic nervous system