Abstract
A potent angiotensin II type-1 receptor blocker, azilsartan, has been reported to reduce blood pressure more effectively than candesartan. Interestingly, azilsartan can also restore the circadian rhythm of blood pressure. We hypothesized that azilsartan could also improve salt sensitivity; thus, we examined the effect of azilsartan on sodium handling in renal tubules. Subtotal nephrectomized C57BL/6 mice received azilsartan (1.0 mg/kg/day), candesartan (0.3 mg/kg/day), or vehicle via the oral route in conjunction with a normal- (0.3%) or high-salt (8.0%) diet. Two weeks later, the azilsartan group showed significantly lower blood pressure during the light period than the candesartan and vehicle groups (azilsartan: 103.1 ± 1.0; candesartan: 111.7 ± 2.7; vehicle: 125.5 ± 2.5 mmHg; P < 0.05; azilsartan or candesartan vs. vehicle). The azilsartan group also showed higher urinary fractional excretion of sodium during the dark period than the candesartan and vehicle groups (azilsartan: 21.37 ± 3.69%; candesartan: 14.17 ± 1.42%; vehicle: 13.85 ± 5.30%; P < 0.05 azilsartan vs. candesartan or vehicle). A pressure—natriuresis curve demonstrated that azilsartan treatment restored salt sensitivity. Immunofluorescence and western blotting showed lower levels of Na+-H+ exchanger-3 (NHE3) protein (the major sodium transporter in renal proximal tubules) in the azilsartan group, but not in the candesartan or vehicle groups. However, azilsartan did not affect NHE3 transcription levels. Interestingly, we did not observe increased expression of downstream sodium transporters, which would have compensated for the increased flow of sodium and water due to non-absorption by NHE3. We also confirmed the mechanism stated above using cultured opossum kidney proximal tubular cells. Results revealed that a proteasomal inhibitor (but not a lysosomal inhibitor) blocked the azilsartan-induced decrease in NHE3 protein expression, suggesting that azilsartan increases NHE3 ubiquitination. In conclusion, azilsartan (but not candesartan) improved salt sensitivity possibly by decreasing NHE3 expression via ubiquitin—proteasomal degradation.
Highlights
Hypertension is an important risk factor for cardiovascular and renal diseases
In contrast to the high-salt diet, neither azilsartan nor candesartan reduced blood pressure compared with the vehicle control when the mice were exposed to a normal-salt diet (Fig 1B)
Ubiquitination plays a major part in proteasomal degradation; we examined whether Na+-H+ exchanger-3 (NHE3) ubiquitination was accelerated by azilsartan
Summary
Hypertension is an important risk factor for cardiovascular and renal diseases. It is evident in countries with a “westernized” lifestyle, in which %25% of the adult population is affected by hypertension [1].Sodium intake has been demonstrated to be a modifiable cause of hypertension, which can lead to undesirable cardiovascular and renal outcomes [2]. Hypertension is an important risk factor for cardiovascular and renal diseases. It is evident in countries with a “westernized” lifestyle, in which %25% of the adult population is affected by hypertension [1]. Salt-sensitive individuals (normotensive and hypertensive) exhibit variable blood pressure levels after salt loading or restriction. Salt-sensitive patients are more prone to cardiovascular events and renal events than non-saltsensitive hypertensive patients [3]. Disturbances in the circadian rhythm of blood pressure (an independent predictor of cardiovascular events [4,5,6,7,8,9]) are closely associated with sensitivity to salt. “non-dipper” hypertensive patients (i.e., those whose blood pressure does not decrease during the night) are more likely to exhibit salt sensitivity [10, 11]
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