[Examination of genetic susceptibility for essential hypertension].
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Body Mass Index↗
Biomedical subjects
Jitsuo Higaki
Publications and source records attributed to Jitsuo Higaki.
In vivo administration of a nuclear transcription factor-kappaB decoy suppresses experimental crescentic glomerulonephritis.
Glomerular expression of cytokines, interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-alpha), together with leukocytic infiltration, are prominent features in crescentic glomerulonephritis. Because these cytokines are targets for nuclear transcription factor-kappaB (NF-kappaB), the use of NF-kappaB decoy oligodeoxynucleotide (ODN) treatment was evaluated in an experimental disease model. Crescentic glomerulonephritis was induced in primed Wistar rats by injection of sheep antiglomerular basement membrane serum. Thirty minutes after injection, rats were anesthetized and the left kidney was perfused with NF-kappaB decoy ODN or scrambled ODN control mixed with a virus-liposome complex, and then killed 7 d later. Animals given the scrambled control ODN developed severe glomerulonephritis by day 7 with heavy proteinuria, glomerular crescents and interstitial lesions, marked leukocytic infiltration, and upregulated renal expression of cytokines (IL-1 and TNF-alpha) and adhesion molecules (intercellular adhesion molecule-1). In contrast, NF-kappaB decoy ODN treatment substantially inhibited the disease with a 50% reduction in proteinuria, a threefold reduction in histologic damage, a 50% reduction in leukocytic infiltration, and a 50 to 80% reduction in the renal expression of cytokines and leukocyte adhesion molecules. In conclusion, this study has demonstrated that NF-kappaB plays a key role in cytokine-mediated renal injury and that NF-kappaB decoy ODN treatment has clear therapeutic potential in rapidly progressive glomerulonephritis.
Animals↗
Targeted gene therapy for rat glomerulonephritis using HVJ-immunoliposomes.
BACKGROUND: Kidney targeted gene transfer has been attempted by many researchers over the last 10 years; however, unfortunately, no reliable technique for gene transfer to the kidney has been established. At experimental level several in vivo gene transfer methods have been reported. METHODS: We were the first to report successful in vivo gene transfer into the kidney using the HVJ-liposome method. Since then, this method has been modified to achieve highly efficient gene transfer. In this study, we have developed a renal glomerulus-specific gene transfer method using HVJ-liposomes with anti-Thy 1 antibody, OX-7. RESULTS: Following systemic delivery of fluoroisothiocyanate (FITC)-labeled oligodeoxynucleotides (ODN) by HVJ-liposomes coupled with OX-7, we observed fluorescence in renal glomeruli from 2 h post-administration. To examine the efficacy of this delivery system, NF-kappaB or scrambled (SD) decoy ODN was administered by HVJ-liposomes coupled with OX-7 into a crescent glomerulonephritis, anti-glomerular basement membrane (GBM) model. Animals given SD decoy ODN developed severe glomerulonephritis by day 7 with heavy albuminuria, glomerular crescent formation and up-regulated renal expression of IL-1beta and ICAM-1. In contrast, NF-kappaB decoy ODN treatment substantially inhibited the disease with a reduction in alubuminuria, histological damage and the renal expression of inflammatory cytokines. CONCLUSIONS: This study has demonstrated that systemic delivery of HVJ-liposomes coupled with OX-7 results in efficient ODN transfer in rat glomeruli. NF-kappaB, but not SD decoy ODN administered systemically via HVJ-liposomes complexed with OX-7 showed clear therapeutic potential for glomerulonephritis. This novel ODN transfer method combined with decoy strategy has the potential to lead to the establishment of a new therapeutic approach to glomerular diseases.
Animals↗
Changes in autonomic activity and baroreflex sensitivity with the hypertension process and age in rats.
1. Autonomic activity and baroreflex sensitivity (BRS) were compared in age-matched conscious groups of Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. Male WKY rats, SHR and SHRSP aged 4-30 weeks were used. Autonomic activity and BRS were estimated by power spectral and cross-spectral analysis of systolic blood pressure (SBP) and SBP-SBP (SS) interval fluctuations, respectively. 3. The time-course of heart rate (HR), SBP, the amplitude of the low-frequency component of SBP fluctuation (SBP-LF; prazosin-sensitive index) and the amplitude of the high-frequency component of the SS interval fluctuation (SS-HF; atropine-sensitive index) consisted of two periods. In the first period (up to 10 or 15 weeks of age), BP, SBP-LF and SS-HF increased with age. The order of SBP-LF was SHRSP > SHR > WKY rats throughout this period. During the second period, BP was sustained at certain levels in all strains, but changes in SBP-LF and SS-HF with age were different among strains. In particular, in SHRSP, SBP-LF markedly decreased with age after 10 weeks. Baroreflex sensitivity in WKY rats increased gradually with age, whereas the BRS in SHR and SHRSP decreased before 6 weeks of age and remained lower than that in WKY rats. 4. In conclusion, the present study shows that both prazosin-sensitive and atropine-sensitive indices are associated with the elevation of BP in all strains studied. However, hypertension after 15 weeks of age in SHRSP is sustained despite a paradoxical reduction in sympathetic activity with an abnormal control of BRS. Therefore, the contribution of autonomic activity to hypertension may be discussed separately as a developmental period and a sustained period.
Aging↗
Successful treatment of obstructive sleep apnea syndrome improves autonomic nervous system dysfunction.
Autonomic nervous system (ANS) dysfunction may be implicated in the subsequent development of cardiovascular disease in patients with obstructive sleep apnea syndrome (OSAS). To confirm the relation between OSAS and ANS dysfunction, we prospectively investigated ANS function in 7 patients with moderate or severe OSAS; 7 healthy age-matched volunteers were for control. We also studied ANS function before and after treatment in the patients with OSAS to evaluate the effect of OSAS treatment on ANS dysfunction. The body mass index of patients with OSAS was 32.2 (27.4-45) (median [range]) kg/m2. The patients were treated by nasal continuous positive airway pressure (n = 5) or uvulopalatopharyngoplasty (n = 2). The apnea/hypopnea index decreased markedly from 42.1 (30.6-77.2) events/hr of sleep before treatment to 2.3 (1.4-3.8) after treatment. To evaluate ANS function, the coefficient of variation of the RR interval (CV-RR) and corrected QT (QTc) interval on the electrocardiogram at rest and the heart rate (HR) responses to blood pressure (BP) changes during the Valsalva maneuver were studied. Baseline HR of OSAS patients was significantly higher than that of the control subjects (p < .05). The Valsalva ratio (VR), baroreflex sensitivity (BRS), and CV-RR values in patients with OSAS were significantly lower than those of the control subjects (all, p < .005). However, there were no significant differences in systolic and diastolic BP or QTc intervals. After treatment, VR, BRS, and CV-RR values increased significantly compared with those before treatment in patients with OSAS (all, p < .05). There were no significant differences in systolic and diastolic BP, HR, or QTc intervals measured before and after treatment. These results suggest that impaired ANS function is present in patients with OSAS and can be improved by successful treatment of OSAS.
Adult↗