Function and regulation of epithelial sodium transporters in the kidney of a salt-sensitive hypertensive rat model

Li, Jianping; Wang, Donna H.

doi:10.1097/hjh.0b013e3280a8b87d

Cited by 13 publications

(9 citation statements)

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“…These data show that selective knockdown of neuronal TRPV1 enhances prohypertensive effects induced by salt loading and that pressor effects of TRPV1 shRNA may be mediated, at least in part, by enhancement of the sympatho-excitatory response. We have previously shown that neonatal degeneration of TRPV1-expressing sensory nerves increased salt sensitivity of arterial pressure as these rats grew into adulthood [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . However, the systemic sensory denervation used in these previous studies precluded us from making conclusions about whether the observed effect was due to the removal of TRPV1 or other proteins co-expressed in the same nerves innervating any specific organs or tissues [21,22] .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, defining the role of TRPV1-positive sensory nerves in the regulation of blood pressure and salt sensitivity will be useful. We have shown previously that the degeneration of TRPV1-expressing sensory nerves throughout the neonatal body by subcutaneous injection of capsaicin, a selective TRPV1 agonist, leads to increased salt sensitivity of arterial pressure, indicating that TRPV1-positive sensory nerves play a counter-regulatory role against salt-induced increases in blood pressure [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . The underlying mechanism of anti-hypertensive effects of TRPV1 may involve its counter-balancing role against the activation of the renin-angiotensin-aldosterone system [7][8][9] , sympathetic nervous system [10] , endothelin system [11,12] , superoxide generation system [13,14] , and epithelial sodium transporters [15] .…”

Section: Introductionmentioning

confidence: 99%

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Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord

Wang

2011

Acta Pharmacol Sin

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Aim: To investigate the effects of selective knockdown of TRPV1 channels in the lower thoracic and upper lumbar segments of spinal cord, dorsal root ganglia (DRG) and mesenteric arteries on rat blood pressure responses to high salt intake. Methods: TRPV1 short-hairpin RNA (shRNA) was delivered using intrathecal injection (6 μg·kg -1 ·d -1 , for 3 d). Levels of TRPV1 and tyrosine hydroxylase expression were determined by Western blot analysis. Systolic blood pressure and mean arterial pressure (MAP) were examined using tail-cuff and direct arterial measurement, respectively. Results: In rats injected with control shRNA, high-salt diet (HS) caused higher systolic blood pressure compared with normal-salt diet (NS) (HS:149±4 mmHg; NS:126±2 mmHg, P<0.05). Intrathecal injection of TRPV1 shRNA signifi cantly increased the systolic blood pressure in both HS rats and NS rats (HS:169±3 mmHg; NS:139±2 mmHg). The increases was greater in HS rats than in NS rats (HS: 13.9%±1.8%; NS: 9.8±0.7, P<0.05). After TRPV1 shRNA treatment, TRPV1 expression in the dorsal horn and DRG of T8-L3 segments and in mesenteric arteries was knocked down to a greater extent in HS rats compared with NS rats. Blockade of α1-adrenoceptors abolished the TRPV1 shRNA-induced pressor effects. In rats injected with TRPV1 shRNA, level of tyrosine hydroxylase in mesenteric arteries was increased to a greater extent in HS rats compared with NS rats. Conclusion: Selective knockdown of TRPV1 expression in the lower thoracic and upper lumbar segments of spinal cord, DRG, and mesenteric arteries enhanced the prohypertensive effects of high salt intake, suggesting that TRPV1 channels in these sites protect against increased salt sensitivity, possibly via suppression of sympatho-excitatory responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord

Wang

2011

Acta Pharmacol Sin

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“…Although numerous systems can influence BP over the short term, long-term BP regulation depends on the renal excretion of sodium (22). An increased BP in response to dietary sodium (salt sensitivity) has been widely reported in humans and animals and is proposed as a major factor in the pathogenesis of hypertension (4).…”

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confidence: 99%

Salt sensitivity in experimental thyroid disorders in rats

Pérez-Abud

Rodríguez-Gómez

Villarejo

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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This study assessed salt sensitivity, analyzing the effects of an increased saline intake on hemodynamic, morphological, and oxidative stress and renal variables in experimental thyroid disorders. Six groups of male Wistar rats were used: control, hypothyroid, hyperthyroid, and the same groups treated with salt (8% via food intake). Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 6 wk. Finally, BP and HR were recorded directly, and morphological, metabolic, plasma, and renal variables were measured. High-salt intake increased BP in thyroxine-treated rats but not in control or hypothyroid rats. High-salt intake increased cardiac mass in all groups, with a greater increase in hyperthyroid rats. Urinary isoprostanes and H 2O2 were higher in hyperthyroid rats and were augmented by high-salt intake in all groups, especially in hyperthyroid rats. High-salt intake reduced plasma thyroid hormone levels in hyperthyroid rats. Proteinuria was increased in hyperthyroid rats and aggravated by high-salt intake. Urinary levels of aminopeptidases (glutamyl-, alanyl-, aspartyl-, and cystinylaminopeptidase) were increased in hyperthyroid rats. All aminopeptidases were increased by salt intake in hyperthyroid rats but not in hypothyroid rats. In summary, hyperthyroid rats have enhanced salt sensitivity, and high-salt intake produces increased BP, cardiac hypertrophy, oxidative stress, and signs of renal injury. In contrast, hypothyroid rats are resistant to salt-induced BP elevation and renal injury signs. Urinary aminopeptidases are suitable biomarkers of renal injury. salt intake; hyperthyroidism; hypothyroidism; aminopeptidases; blood pressure RENAL FUNCTION AND SALT AND water metabolism can be considerably impaired by thyroid disorders (3, 46). Some authors reported that hypothyroid rats have a lesser ability to concentrate urine and show increased natriuresis after salt or water loading (10,18,25,39) and have a reduced capacity to conserve sodium, which produces a negative sodium balance and death when subjected to dietary sodium restriction (13). However, our group did not observe increased sodium excretion in hypothyroid methimazole-treated rats under some of the above conditions (44) or in pressure-diuresis-natriuresis studies (43). On the other hand, thyroxine (T 4 )-treated rats showed changes in renal hemodynamics and sodium resorption (46), increased blood volume (34), polydipsia/polyuria (15), reduced ability to excrete sodium after hypertonic saline loading (44), and a blunted pressure-diuresis-natriuresis response (43).These data indicate that thyroid disorders are accompanied by major changes in renal sodium handling.Hypothyroidism reduces blood pressure (BP) and prevents experimental hypertension (46), whereas T 4 administration to rats increases BP (6) and accelerates the course of hypertension (46). Although numerous systems can influence BP over the short term, long-term BP regulation depends on the renal excretion of sodium (22). An increased BP in response to dietary sodium (sal...

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“…Salt-induced NHE3 suppression is more impaired in Dahl salt-sensitive rats than in Dahl salt-resistant rats (68). NKCC2 activity in thick ascending limb is also upregulated in salt-sensitive rats (3,10,66). Single-nucleotide polymorphisms involving NKCC2 activation in thick ascending limb are associated with salt-sensitive hypertension in humans (123).…”

Section: Animal Models Of Salt-sensitive Hypertensionmentioning

confidence: 99%

“…The last fraction is reabsorbed via epithelial Na ϩ channels (ENaC) in the CNT/CD. Na ϩ /H ϩ exchanger (NHE)3 in proximal tubules (62,68) and NKCC2 in the thick ascending limb (3,10,66) are associated with salt-sensitive hypertension in animal models. Salt-induced NHE3 suppression is more impaired in Dahl salt-sensitive rats than in Dahl salt-resistant rats (68).…”

Section: Animal Models Of Salt-sensitive Hypertensionmentioning

confidence: 99%

Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways

Nishimoto

Fujita

2015

American Journal of Physiology-Renal Physiology

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Nishimoto M, Fujita T. Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways. Am J Physiol Renal Physiol 308: F377-F387, 2015. First published December 17, 2014 doi:10.1152/ajprenal.00477.2013.-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 ␤ 2-adrenergic stimulant-glucocorticoid receptor (GR)-with-no-lysine kinase (WNK)4-Na ϩ -Cl Ϫ 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. ␤ 2-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 ϩ -Cl Ϫ cotransporters in the DCT and elevated Na ϩ 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 ϩ 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.salt-sensitive hypertension; mineralocorticoid receptor; glucocorticoid receptor; Ras-related C3 botulinum toxin substrate 1; sympathetic nervous system HIGH LEVELS of dietary salt intake can induce hypertension, with salt restriction being one of the most effective treatments for this condition (32,72,79). Hypertensive patients, however, exhibit a large spectrum of salt sensitivity (71), with the mechanisms determining salt sensitivity as yet incompletely understood.Several factors influence salt sensitivity, including the activities of the sympathetic nervous system (SNS), the reninangiotensin system (RAS), aldosterone, and insulin. In the Guytonian model, dysfunctional excretion of renal Na ϩ plays a major role in Na ϩ retention and salt-sensitive hypertension (42). Several genes have been found to cause rare Mendelian forms of human hypertension (134), with these findings providing insights into the basic mechanisms of human hypertension and highlighting the key role of altered Na ϩ handling by the kidneys as a final common pathway in the pathogenesis of hypertension. In...

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Function and regulation of epithelial sodium transporters in the kidney of a salt-sensitive hypertensive rat model

Cited by 13 publications

References 36 publications

Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord

Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord

Salt sensitivity in experimental thyroid disorders in rats

Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways

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