• Childhood Kidney Diseases
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• v.15 no.2
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• pp.125-137
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• 2011

Purpose : Men are generally more prone to chronic renal disease and progression to end stage renal disease than women. The purpose of this study is to prove the effect of gender and sex hormone on renal fibrosis in mice with unilateral ureteral obstruction (UUO) and to elucidate the specific underlying mechanisms. Methods :We compared the expression of ${\alpha}$-smooth muscle actin (${\alpha}$-SMA) in female and male mice with complete UUO (day 7). After this, we estimated the changes of renal fibrosis in the female mice with oophorectomy and in the female mice with oophorectomy and replacement of $17{\beta}$-estradiol, respectively. Results : The level of ${\alpha}$-SMA in the female kidney with UUO was significantly lower than that in the male kidney with UUO. oophorectomy and replacement of $17{\beta}$-estradiol did not change the expression of angiotensin II type 1 (AT1) receptor in the female kidney with UUO, whereas the expression of angiotensin II type 2 (AT2) receptor was significantly more elevated in the intact female (IF) and the oophorectomized female with estrogen (OF+E) than that in the oophorectomized female (OF). The expressions of inducible nitric oxide synthase (iNOS) in the IF and OF+E mice were significantly more elevated than that in the OF mice, which was similar to the expression of AT2 receptor. Conclusion : The female gender is associated with resistance to renal fibrosis in obstructive uropathy and this gender difference may originate from the existence of $17{\beta}$-estradiol, which has an anti-fibrotic effect via upregulation of the AT2 receptor and iNOS.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.10 no.11
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• pp.3473-3479
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• 2009

The pharmacological profile of KR-31081, a newly synthesized AT1 receptor antagonist, was evaluated in pithed rats, conscious renal hypertensive rats (RHRs) and conscious furosemide-treated beagle dogs. In pithed rats, KR-31081 (i.v.) induced a non-parallel right shift in the dose-pressor response curve to angiotensin II (ID50: 0.05 mg/kg) with a dose-dependent reduction in the maximum responses; this antagonistic effect was about 40 times more potent than losartan (ID50: 1.74 mg/kg) which showed competitive antagonism. KR-31081 did not alter the responses induced by other agonists such as norepinephrine and vasopressin. In RHRs, orally given KR-31081 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a higher potency to losartan (ED20: 0.30 and 3.36 mg/kg, respectively). In furosemide-treated dogs, orally given KR-31081 produced a dose-dependent and long-lasting (>8h) antihypertensive effect with a rapid onset of action (time to Emax: 1-1.5 h) and 20-fold greater potency than losartan (ED20: 0.41 and 8.13 mg/kg, respectively). These results suggest that KR-31081 is a potent, orally active AT1 receptor antagonist useful for the research and diagnostic tools as an added exploratory potential.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.4
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• pp.413-423
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• 1997

The importance of the kidney in the development of hypertension was first demonstrated by Goldblatt and his colleagues more than fifty years ago. Many hormones and other regulatory factors have been proposed to play a major role in the development of hypertension. Among these factors angiotensia II (ANG II) is closely involved in renal hypertension development since it directly regulates $Na^+$ reabsorption in the renal proximal tubule. Thus the aim of the present study was to examine signaling pathways of low dose of ANC II on the $Na^+$ uptake of primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined seum-free medium. The results were as follows: 1) $10^{-11}$ M ANG II has a significant stimulatory effect on growth as compared with control. Alkaline phosphatase exhibited significantly increased activity. However, leucine aminopeptidase and ${\gamma}-glutamyl$ transpeptidase activity were not significant as compared with control. In contrast to $10^{-11}$ M ANG II stimulated $Na^+$ uptake $(108.03{\pm}2.16% of that of control)$, $10^{-9}$ M ANG II inhibited ($92.42{\mu}2.23%$ of that of control). The stimulatory effect of ANG II on $Na^+$ uptake was amiloride-sensitive and inhibited by losartan (ANG II receptor subtype 1 antagonist) and not by PD123319 (ANG II receptor subtype 2 antagonist). 2) Pertussis toxin (PTX) alone inhibited $Na^+$ uptake by $85.52{\pm}3.52%$ of that of control. In addition, PTX pretreatment prevented the AMG II-induced stimulation of $Na^+$ uptake. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), forskolin, and isobutylmethylxanthine (IBMX) alone inhibited $Na^+$ uptake by $88.79{\pm}2.56,\;80.63{\pm}4.38,\;and\;84.47{\pm}4.74%$ of that of control, respectively, and prevented the ANG II-induced stimulation of $Na^+$ uptake. However, $10^{-11}$ M ANG II did not stimulate cAMP production. 3) The addition of 12-O-te-tradecanoylphorbol-13-acetate (TPA, 0.01 ng/ml) to the PTCs produced significant increase in $Na^+$ uptake ($114.43{\pm}4.05%$ of that of control). When ANG II and TPA were added together to the PTCs, there was no additive effect on $Na^+$ uptake. Staurosporine alone had no effect on $Na^+$ uptake, but led to a complete inhibition of ANG II- or TPA-induced stimulation of Na'uptake. ANG II treatment resulted in a $111.83{\mu}4.51%$ increase in total protein kinase C (PKC) activity. In conclusion, the PTX-sensitive PKC pathway is the main signaling cascade involved in the stimulatory effects of ANG II on $Na^+$ uptake in the PTCs.

• Childhood Kidney Diseases
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• v.12 no.1
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• pp.99-104
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• 2008

Microscopic polyangiitis(MPA) is a systemic necrotizing vasculitis that involves many organ systems including the skin, joint, kidneys, and lungs. In spite of early diagnosis and intensive care, the five-year actuarial patient and kidney survival rates are 65% and 55%. We experienced a case in 7-year-old girl of microscopic polyangiitis presenting with rapidly progressive glomerulonephritis which was confirmed by renal biopsy and positive serum perinuclear antineutrophil cytoplasmic autoantibodies(p-ANCA). The diagnosis of patients first renal biopsy was MPA, p-ANCA-associated crescentic glomerulonephritis. The patients second renal biopsy was done 5 years 6 months later since first renal biopsy, and pathologic diagnosis was chronic sclerosing glomerulonephritis, advanced, due to MPA. We began methylprednisolone pulse therapy, combined with a low dose of cyclophosphamide and plasmapheresis therapy. ACE inhibitor, angiotensin II receptor blocker, and cyclophosphamide were used until now and the patients current age is 14 years old. On admission, the patients laboratory findings showed BUN 117 mg/dL and Cr 2.3 mg/dL, while on the hospital day BUN and Cr values fell to 20.8 mg/dL and 1.6 mg/dL. But renal function was progressed to chronic failure with latest laboratory data BUN 51.7 mg/dL and Cr 3.2 mg/dL. ACE inhibitor, angiotensin II receptor blocker and small dose of immunosuppressant with close observation is the key to maintain the patient survival.

• Proceedings of the Korean Nutrition Society Conference
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• 2002.05a
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• pp.144-144
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• 2002

• The Korean Journal of Pharmacology
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• v.28 no.1
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• pp.61-74
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• 1992

Influence of the blockade of the three major pressor systems-sympathetic nervous system (SNS), renin-angiotensin system (RAS) and vasopressin system-on the pressor responsiveness to norepinephrine (NE), angiotensin II (AII), and vasopressin (VP) as well as on basal blood pressure (BP) levels was investigated in urethane-anesthetized rabbits. To block the SNS and RAS, chlorisondamine (CS) and pirenzepine (PZ), sympathetic ganglionic blockers, and enalapril (ENAL), an inhibitor of angiotensin converting enzyme, respectively were used. And for suppressing the VP system bremazocine (BREM), a kappa opiate receptor agonist shown to suppress plasma levels of VP, was employed. Each of CS (0.4 mg/kg), ENAL (2 mg/kg), and BREM (0.25 mg/kg) produced almost same levels of steady hypotensive state. The hypotensive effect of BREM was significantly attenuated by desmopressin, a synthetic VP-like analogue, suggesting the hypotension being at least in part due to suppression of plasma levels of VP. CS, ENAL and BREM elicited further fall of the BP which had been lowered by ENAL or BREM, CS or BREM, and CS or ENAL, respectively. The hypotension produced by both CS and PZ together with either of ENAL or BREM was more marked than that produced by the three drugs other than CS. CS potentiated the pressor response not only to NE but to AII and VP. The pressor effect of AII was increased by ENAL and BREM, too. The pressor response to VP was also enhanced by BREM. Blockade of ${\alpha}-adrenergic$ receptors with phentolamine or phenoxybenzamine potentiated the pressor response to AII and that to VP. The results on basal BP levels indicate that the three major pressor systems are all participating in control of BP, but SNS has the greatest potential for supporting BP. The finding that blockade of one of the pressor systems induced enhanced pressor responsiveness to the pressor hormone of that particular system as well as to the pressor hormone(s) of the other systems(s) provides evidence for important interactions among the three major pressor systems.

• Nutrition Research and Practice
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• v.11 no.5
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• pp.388-395
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• 2017

BACKGROUND/OBJECTIVES: Although Korean fermented foods contain large amounts of salt, which is known to exacerbate health problems, these foods still have beneficial effects such as anti-hypertension, anti-cancer, and anti-colitis properties. We hypothesized that ganjang may have different effects on blood pressure compared to same concentrations of salt. MATERIALS/METHODS: Sprague-Dawley rats were divided into control (CT), NaCl (NC), and ganjang (GJ) groups and orally administered with 8% NaCl concentration for 9 weeks. The systolic blood pressure (SBP), serum chemistry, $Na^+$ and $K^+$ concentrations and renal gene expressions were measured. RESULTS: The SBP was significantly increased in the NC group compared to the GJ and CT groups. In addition, the $Na^+$ concentration in urine was higher in the GJ and NC groups than the CT group, but the urine volume was increased in the GJ group compared to the other groups. The serum renin levels were decreased in the GJ group compared to the CT group, while the serum aldosterone level was decreased in the GJ group relative to the NC group. The mRNA expression of the renin, angiotensin II type I receptor, and mineralocorticoid receptor were significantly lower in the GJ group compared to other groups. Furthermore, GJ group showed the lowest levels of genes for $Na^+$ transporter in kidney cortex such as $Na^+/K^+$ $ATPase{\alpha}1$ ($NKA{\alpha}1$), $Na^+/H^+$ exchanger 3 (NHE3), $Na^+/HCO_3{^-}$ co-exchanger (NBC), and carbonic anhydrases II (CAII). CONCLUSIONS: The decreased SBP in the GJ could be due to decreased renin and aldosterone levels in serum and increased urinary volume and excretion of $Na^+$ with its transporter gene alteration. Therefore, ganjang may have antihypertensive effect despite its high contents of salt.

• Korean Journal of Clinical Pharmacy
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• v.32 no.2
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• pp.125-132
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• 2022

Background: Fixed-dose combinations have the advantage of improving patient compliance, but may increase the risk of duplicate prescriptions. As the use of fixed-dose combination antihypertensives increases, it is necessary to investigate the current status of class duplication prescriptions (CDP) in patients taking fixed-dose combination antihypertensives in Korea and to identify factors associated with CDP. Methods: We conducted a retrospective observational study using nationally representative claim data. Hypertensive patients aged 20 years or older taking fixed-dose combination antihypertensives were extracted. Among these patients, patients with CDP were identified. A chi-square test was applied to determine the differences between patients with CDP and non-CDP. The associated factors of CDP were identified through multiple logistic regression. Results: Of the 74,165 patients who were prescribed fixed-dose combination antihypertensives, 426 patients (0.6%) with CDP were identified. The most common antihypertensive class associated with CDP was calcium channel blockers (194 patients, 45.5%), followed by angiotensin II receptor blockers (136 patients, 31.9%). Patients aged 75 years or older (odds ratio [OR] 1.83, 95% confidence interval [CI] 1.02-3.52), chronic kidney disease (OR 4.45, 95% CI 2.15-8.25), chronic heart failure (OR 2.71, 95% CI 1.93-3.72), coronary artery disease (OR 2.22, 95% CI 1.60-3.03) and Medical Aid/Patriots and Veterans Insurance (OR 1.49, 95% CI 1.04-2.07) were significantly associated with increased CDP. Conclusions: The factors associated with CDP were the elderly, comorbidities, and low socioeconomic status. Since CDP can result in negative clinical outcomes, active intervention by the pharmacist is warranted.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.135-143
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• 2018

Tumor necrosis $factor-{\alpha}$ ($TNF{\alpha}$) and the angiotensin system are involved in inflammatory diseases and may contribute to acute kidney injury. We investigated the mechanisms by which $TNF{\alpha}$-converting enzyme (TACE) contributes to lipopolysaccharide (LPS)-induced renal inflammation and the effect of TACE inhibitor treatment on LPS-induced cellular injury in human renal proximal tubule epithelial (HK-2) cells. Mice were treated with LPS (10 mg/kg, i.p.) and HK-2 cells were cultured with or without LPS ($10{\mu}g/ml$) in the presence or absence of a type 1 TACE inhibitor ($1{\mu}M$) or type 2 TACE inhibitor ($10{\mu}M$). LPS treatment induced increased serum creatinine, $TNF{\alpha}$, and urinary neutrophil gelatinase-associated lipocalin. Angiotensin II type 1 receptor, mitogen activated protein kinase (MAPK), and TACE increased, while angiotensin-converting enzyme-2 (ACE2) expression decreased in LPS-induced acute kidney injury and LPS-treated HK-2 cells. LPS induced reactive oxygen species and the down-regulation of ACE2, and these responses were prevented by TACE inhibitors in HK-2 cells. TACE inhibitors increased cell viability in LPS-treated HK-2 cells and attenuated oxidative stress and inflammatory cytokines. Our findings indicate that LPS activates renin angiotensin system components via the activation of TACE. Furthermore, inhibitors of TACE are potential therapeutic agents for kidney injury.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.4
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• pp.327-335
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• 2009

The aim of this study was to determine whether losartan, an angiotensin II (Ang II) type 1 ($AT_1$) receptor could influence the CA release from the isolated perfused model of the rat adrenal medulla. Losartan (5${\sim}$50 ${\mu}$M) perfused into an adrenal vein for 90 min produced dose- and time-dependent inhibition of the CA secretory responses evoked by ACh (5.32 mM), high $K^+$ (56 mM, a direct membrane depolarizer), DMPP (100 ${\mu}$M) and McN-A-343 (100 ${\mu}$M). Losartan failed to affect basal CA output. Furthermore, in adrenal glands loaded with losartan (15 ${\mu}$M) for 90 min, the CA secretory responses evoked by Bay-K-8644 (10 ${\mu}$M, an activator of L-type $Ca^{2+}$ channels), cyclopiazonic acid (10 ${\mu}$M, an inhibitor of cytoplasmic $Ca^{2+}$ -ATPase), veratridine (100 ${\mu}$M, an activator of $Na^+$ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations (150${\sim}$300 ${\mu}$M), losartan rather enhanced the CA secretion evoked by ACh. Collectively, these experimental results suggest that losartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization from the rat adrenal medulla, but at high concentration it rather inhibits ACh-evoked CA secretion. It seems that losartan has a dual action, acting as both agonist and antagonist to nicotinic receptors of the rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of losartan may be mediated by blocking the influx of both $Na^+$ and $Ca^{2+}$ into the rat adrenomedullary chromaffin cells as well as by inhibiting the $Ca^{2+}$ release from the cytoplasmic calcium store, which is thought to be relevant to the $AT_1$ receptor blockade, in addition to its enhancement of the CA release.