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Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether the angiotensin II type 1 receptor blocker (ARB) would improve ambulatory shortterm BP variability in hypertensive patients with diabetic nephropathy. A total of 30 patients with type II diabetes, along with hypertension and overt nephropathy, were enrolled in this randomized, two-period, crossover trial of 12 weeks of treatment with losartan (50 mg daily) and telmisartan (40 mg daily). At baseline and at the end of each treatment period, 24-h ambulatory BP monitoring with power spectral analysis of heart rate and measurements of proteinuria, estimated glomerular filtration rate and brachial-ankle pulse wave velocity (baPWV) were performed. After 12 weeks of treatment, 24-h, daytime and nighttime shortterm BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased by telmisartan. Both losartan and telmisartan reduced urinary protein excretion and baPWV. However, compared with losartan, telmisartan significantly decreased urinary protein excretion, baPWV and low-frequency (LF)-to-high-frequency (HF) ratio, an index of sympathovagal balance. Multiple regression analysis showed significant correlations between urinary protein excretion and baPWV, 24-h LF-to-HF ratio, nighttime systolic BP and 24-h short-term systolic BP variability. These results suggest that ARB, particularly telmisartan, is effective in reducing proteinuria in hypertensive patients with overt diabetic nephropathy, partly through inhibitory effects on ambulatory short-term BP variability and sympathetic nerve activity, in addition to its longer duration of action on nighttime BP reduction.

We examined risk factors for coronary heart disease (CHD) by ambulatory blood pressure (BP) monitoring in 72 diabetic hypertensives who were hospitalized for the educational program. The patients were divided into two groups (CHD group, 19 subjects; and non-CHD group, 53 subjects) along with or without co-existing CHD. On ambulatory BP monitoring, no significant differences were found between the groups regarding BP values through the day. However, the CHD group had a significantly greater BP variability than non-CHD group. The result of logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CHD.

The intrarenal renin-angiotensin system plays a crucial role in the regulation of renal circulation and sodium reabsorption through the activation of vascular, glomerular, and tubular angiotensin II type 1 (AT(1)) receptor signaling. We previously cloned a molecule that specifically interacted with the murine AT(1) receptor to inhibit AT(1) receptor signaling, which we named ATRAP (for AT(1) receptor-associated protein). Since murine ATRAP was shown to be highly expressed in the kidney, in the present study we investigated expression and distribution of human ATRAP in normal kidney and renal biopsy specimens from patients with IgA nephropathy. In the normal human kidney, both ATRAP mRNA and protein were widely and abundantly distributed along the renal tubules from Bowman's capsule to the medullary collecting ducts. In all renal tubular epithelial cells, the ATRAP protein colocalized with the AT(1) receptor. In renal biopsy specimens with IgA nephropathy, a significant positive correlation between ATRAP and AT(1) receptor gene expression was observed. There was also a positive relationship between tubulointerstitial ATRAP expression and the estimated glomerular filtration rate in patients with IgA nephropathy. Furthermore, we examined the function of the tubular AT(1) receptor using an immortalized cell line of mouse distal convoluted tubule cells (mDCT) and found that overexpression of ATRAP by adenoviral gene transfer suppressed the angiotensin II-mediated increases in transforming growth factor-β production in mDCT cells. These findings suggest that ATRAP might play a role in balancing the renal renin-angiotensin system synergistically with the AT(1) receptor by counterregulatory effects in IgA nephropathy and propose an antagonistic effect of tubular ATRAP on AT(1) receptor signaling.

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