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Excessive salt intake causes hypertension and heart diseases. B-type natriuretic peptide (BNP) is a surrogate marker of heart disease, and a slightly elevated BNP level is associated with a poor prognosis. Our previous cross-sectional study demonstrated that plasma BNP has a significant positive association with daily salt intake in the general population. However, the relationship between changes in salt intake and changes in plasma BNP remains unknown. We recruited 3051 participants without hypertension or electrocardiogram abnormalities who underwent annual health check-ups for two consecutive years. Clinical parameters, including plasma BNP, were obtained, and daily salt intake was evaluated using urinary samples. Annual changes in these parameters were calculated. The median plasma BNP level was 12.9 pg/mL, and the daily salt intake was 8.73 ± 1.89 g. The annual changes in plasma BNP and daily salt intake were 4.79 ± 36.38% and 2.01 ± 21.80%, respectively. Participants in the highest quartile of annual changes in daily salt intake showed the largest annual changes in plasma BNP. Annual changes in plasma BNP indicated a significant positive association with daily salt intake. Moreover, multiple linear regression analyses revealed that annual changes in plasma BNP showed a significant positive association with daily salt intake after adjustments. Our study showed a significant positive relationship between annual changes in plasma BNP and annual changes in daily salt intake. The suppression of plasma BNP is therefore induced by salt intake restriction. The monitoring of plasma BNP while reducing salt intake may therefore prevent heart diseases and lead to improved prognoses in the general population without heart diseases.

Circadian fluctuation disorder of the intrarenal renin-angiotensin system (RAS) causes that of blood pressure (BP) and renal damage. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen (AGT) filtered through damaged glomeruli regulates intrarenal RAS activity. Furthermore, glomerular permeability is more strongly affected by glomerular hypertension than by systemic hypertension. Thus, we aimed to clarify whether the circadian rhythm of intrarenal RAS activity is influenced by AGT filtered through damaged glomeruli due to glomerular capillary pressure. Rats with adriamycin nephropathy and an impaired glomerular filtration barrier were compared with control rats. In adriamycin nephropathy rats, olmesartan medoxomil (an angiotensin II type 1 receptor blocker) or hydralazine (a vasodilator) was administered, and the levels of intrarenal RAS components in the active and rest phases were evaluated. Moreover, the diameter ratio of afferent to efferent arterioles (A/E ratio), an indicator of glomerular capillary pressure, and the glomerular sieving coefficient (GSC) based on multiphoton microscopy in vivo imaging, which reflects glomerular permeability, were determined. Mild renal dysfunction was induced, and the systemic BP increased, resulting in increased A/E ratios in the adriamycin nephropathy rats compared with the control rats. Fluctuations in intrarenal RAS activity occurred in parallel with circadian fluctuations in glomerular capillary pressure, which disappeared with olmesartan treatment and were maintained with hydralazine treatment. Furthermore, the GSCs for AGT also showed similar changes. In conclusion, intrarenal RAS activity is influenced by the filtration of liver-derived AGT from damaged glomeruli due to circadian fluctuation disorder of the glomerular capillary pressure.

Abnormal blood pressure (BP) variability (BPV), occurring as beat-to-beat, 24 h, and day-to-day fluctuations, is related to target organ damage. However, the associations between abnormal BPV and renal structural changes have not been clearly investigated. We evaluated the day time and night time BP s.d. and average real variability (ARV), which reflected short-term BPV, the night time to day time (N/D) ratio of systolic BP (SBP), and the 7-day BPV, in 29 normotensive IgA nephropathy (IgAN) patients. We further compared the results with renal structural changes. The degree of arteriosclerosis was positively correlated with age, s.d. of night time SBP and the N/D ratio of SBP, and was negatively correlated with the estimated glomerular filtration rate (eGFR). The degree of arteriolar hyalinosis was positively correlated with age, night time SBP, s.d. of day time and night time SBP, day time and night time ARV, the N/D ratio of SBP and 7-day SBP, and was negatively correlated with the eGFR. A multiple linear regression analysis revealed that the level of arteriolar hyalinosis, but not arteriosclerosis, was associated with the s.d. of night time SBP (β=0.63, P

Activation of the intrarenal renin-angiotensin system (RAS) has a critical role in the pathophysiology of the circadian rhythm of blood pressure (BP) and renal injury, independent of circulating RAS. Although it is clear that the circulating RAS has a circadian rhythm, reports of a circadian rhythm in tissue-specific RAS are limited. Clinical studies evaluating intrarenal RAS activity by urinary angiotensinogen (AGT) levels have indicated that urinary AGT levels were equally low during both the daytime and nighttime in individuals without chronic kidney disease (CKD) and that urinary AGT levels were higher during the daytime than at nighttime in patients with CKD. Moreover, urinary AGT levels of the night-to-day (N/D) ratio of urinary AGT were positively correlated with the levels of N/D of urinary protein, albumin excretion and BP. In addition, animal studies have demonstrated that the expression of intrarenal RAS components, such as AGT, angiotensin II (AngII) and AngII type 1 receptor proteins, increased and peaked at the same time as BP and urinary protein excretion during the resting phase, and the amplitude of the oscillations of these proteins was augmented in a chronic progressive nephritis animal compared with a control. Thus, the circadian rhythm of intrarenal RAS activation may lead to renal damage and hypertension, which both are associated with diurnal variations in BP. It is possible that augmented glomerular permeability increases AGT excretion levels into the tubular lumen and that circadian fluctuation of glomerular permeability influences the circadian rhythm of the intrarenal RAS.

We report that disturbance to the circadian rhythm of urinary angiotensinogen (AGT) excretion may lead to renal damage, hypertension and diurnal blood pressure (BP) variations. We aim to clarify the circadian rhythm of the intrarenal renin-angiotensin system (RAS) and its contribution to renal damage, hypertension and BP variations, and to evaluate whether the administration of RAS blockers influences the circadian rhythms of intrarenal RAS components. Anti-thymocyte serum (ATS) nephritis rats were used as a chronic progressive glomerulonephritis model (group A) and compared with control rats (group C). Other rats with ATS nephritis received olmesartan medoxomil (an angiotensin II (AngII) type 1 receptor (AT1R) blocker; group AO) or hydralazine (a vasodilator; group AH). The levels of intrarenal RAS components were evaluated every 6 h. The expression levels of intrarenal AGT, AngII and AT1R were increased in group A and peaked at the same time as BP and urinary protein excretion during the rest phase. The amplitude of the circadian fluctuation of these proteins was more increased in group A than in group C. The circadian fluctuation of these proteins was reduced in groups AO and AH. However, renal function, proteinuria and augmentation of intrarenal RAS components were reduced only in group AO. Intrarenal RAS components, such as AGT, AngII and AT1R proteins, were increased and the amplitude of the oscillations of these proteins was augmented in ATS nephritis rats. Interestingly, renal damage may be linked to the activation of the intrarenal RAS independent of the amplitude of its oscillations and BP.