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Effect of Bilirubin on Triglyceride Synthesis in Streptozotocin-Induced Diabetic Nephropathy.

Jianwei XU ; Eun Seong LEE ; Seon Ha BAEK ; Shin Young AHN ; Sejoong KIM ; Ki Young NA ; Dong Wan CHAE ; Ho Jun CHIN

Journal of Korean Medical Science.2014;29(Suppl 2):S155-S163. doi:10.3346/jkms.2014.29.S2.S155

We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-beta1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRalpha, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRalpha and SREBP-1 expression and oxidative stress.
Animals ; Bilirubin/pharmacology/*therapeutic use ; Cell Line, Tumor ; Creatine/blood ; Diabetes Mellitus, Experimental/chemically induced/complications/*pathology ; Diabetic Nephropathies/*drug therapy/etiology ; Disease Models, Animal ; Kidney/pathology ; Lipoproteins, HDL/blood ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NADPH Oxidase/metabolism ; Orphan Nuclear Receptors/antagonists & inhibitors/genetics/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Streptozocin/toxicity ; Triglycerides/analysis/*biosynthesis/blood

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Bilirubin Activates Transcription of HIF-1alpha in Human Proximal Tubular Cells Cultured in the Physiologic Oxygen Content.

Sung Gyun KIM ; Shin Young AHN ; Eun Seong LEE ; Sejoong KIM ; Ki Young NA ; Dong Wan CHAE ; Ho Jun CHIN

Journal of Korean Medical Science.2014;29(Suppl 2):S146-S154. doi:10.3346/jkms.2014.29.S2.S146

The expression of hypoxia-inducible factor (HIF) is influenced by reactive oxygen species (ROS). Effect of bilirubin on HIF-1 expression in proximal tubular cells was investigated under physiological oxygen concentration, which is relative hypoxic condition mimicking oxygen content in the medulla of renal tissue. The human kidney (HK2) cells were cultured in 5% oxygen with or without bilirubin. HIF-1alpha protein expression was increased by bilirubin treatment at 0.01-0.2 mg/dL concentration. The messenger RNA expression of HIF-1alpha was increased by 1.69+/-0.05 folds in the cells cultured with 0.1 mg/dL bilirubin, compared to the control cells. The inhibitors of PI3K/mTOR, PI3K/AKT, and ERK 1/2 pathways did not attenuate increased HIF-1alpha expression by bilirubin. HIF-1alpha expression decreased by 10 microM exogenous hydrogen peroxide (H2O2); scavenger of ROS with or without bilirubin in the HK2 cells increased HIF-1alpha concentration more than that in the cells without bilirubin. Exogenous H2O2 decreased the phosphorylation of P70S6 kinase, which was completely reversed by bilirubin treatment. Knockdown of NOX4 gene by small interfering RNA (siRNA) increased HIF-1alpha mRNA expression. In coonclusion, bilirubin enhances HIF-1alpha transcription as well as the up-regulation of HIF-1alpha protein translation through the attenuation of ROS and subunits of NADPH oxidase.
Bilirubin/*pharmacology ; Cell Line ; Epithelial Cells/cytology/metabolism ; Humans ; Hydrogen Peroxide/toxicity ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Kidney Tubules, Proximal/cytology ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; NADPH Oxidase/antagonists & inhibitors/genetics/metabolism ; Oxygen/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Transcriptional Activation/*drug effects ; Up-Regulation/drug effects

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Cobalt Chloride Attenuates Oxidative Stress and Inflammation through NF-kappaB Inhibition in Human Renal Proximal Tubular Epithelial Cells.

Se Won OH ; Yun Mi LEE ; Sejoong KIM ; Ho Jun CHIN ; Dong Wan CHAE ; Ki Young NA

Journal of Korean Medical Science.2014;29(Suppl 2):S139-S145. doi:10.3346/jkms.2014.29.S2.S139

We evaluated the effect of cobalt chloride (CoCl2) on TNF-alpha and IFN-gamma-induced-inflammation and reactive oxygen species (ROS) in renal tubular epithelial cells (HK-2 cells). We treated HK-2 cells with CoCl2 before the administration of TNF-alpha/IFN-gamma. To regulate hemeoxygenase-1 (HO-1) expression, the cells were treated CoCl2 or HO-1 siRNA. CoCl2 reduced the generation of ROS induced by TNF-alpha/IFN-gamma. TNF-alpha/IFN-gamma-treated-cells showed an increase in the nuclear translocation of phosphorylated NF-kappaBp65 protein, the DNA-binding activity of NF-kappaBp50 and NF-kappaB transcriptional activity and a decrease in IkappaBalpha protein expression. These changes were restored by CoCl2. We noted an intense increase in monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES) production in TNF-alpha/IFN-gamma-treated cells. We demonstrated that this effect was mediated through NF-kappaB signaling because an NF-kappaB inhibitor significantly reduced MCP-1 and RANTES production. CoCl2 effectively reduced MCP-1 and RANTES production. The expression of HO-1 was increased by CoCl2 and decreased by HO-1 siRNA. However, knockdown of HO-1 by RNA interference did not affect MCP-1 or RANTES production. We suggest that CoCl2 has a protective effect on TNF-alpha/IFN-gamma-induced inflammation through the inhibition of NF-kappaB and ROS in HK-2 cells. However, CoCl2 appears to act in an HO-1-independent manner.
Cell Line ; Chemokine CCL2/metabolism ; Chemokine CCL5/metabolism ; Cobalt/*pharmacology ; Epithelial Cells/cytology/metabolism ; Heme Oxygenase-1/antagonists & inhibitors/genetics/metabolism ; Humans ; *Inflammation ; Interferon-gamma/pharmacology ; Kidney Tubules, Proximal/cytology ; NF-kappa B/antagonists & inhibitors/genetics/*metabolism ; NF-kappa B p50 Subunit/genetics/metabolism ; Oxidative Stress/*drug effects ; Phosphorylation ; Protein Binding ; RNA Interference ; RNA, Small Interfering/metabolism ; Transcription Factor RelA/metabolism ; Tumor Necrosis Factor-alpha/pharmacology

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Estimated Amount of 24-Hour Urine Sodium Excretion Is Positively Correlated with Stomach and Breast Cancer Prevalence in Korea.

Jung Hwan PARK ; Yong Chul KIM ; Ho Seok KOO ; Se Won OH ; Suhnggwon KIM ; Ho Jun CHIN

Journal of Korean Medical Science.2014;29(Suppl 2):S131-S138. doi:10.3346/jkms.2014.29.S2.S131

Stomach cancer is one of the most common cancers in Korea. The aim of this study was to identify the association between the prevalence of cancer, particularly stomach cancer, and the amount of 24-hr urine sodium excretion estimated from spot urine specimens. The study included 19,083 subjects who took part in the Korean National Health and Nutritional Examination Survey between 2009 and 2011. The total amount of urine sodium excreted in a 24-hr period was estimated by using two equations based on the values for spot urine sodium and creatinine. In subjects who had an estimated 24-hr urine sodium excretion of more than two standard deviations above the mean (group 2), the prevalence of stomach cancer was higher than in subjects with lower 24-hr sodium excretion (group 1). By using the Tanaka equation to estimate it, the prevalence of stomach cancer was 0.6% (114/18,331) in group 1, whereas it was 1.6% (9/568) in group 2 (P=0.006). By using the Korean equation, the prevalence was 0.6% (115/18,392) in group 1, and 1.6% in group 2 (8/507) (P=0.010). By using the Tanaka equation, breast cancer in women is more prevalent in group 2 (1.9%, 6/324) than group 1 (0.8%, 78/9,985, P=0.039). Higher salt intake, as defined by the estimated amount of 24-hr urine sodium excretion, is positively correlated with a higher prevalence of stomach or breast cancer in the Korean population.
Adult ; Aged ; Algorithms ; Breast Neoplasms/*epidemiology/pathology ; Creatine/urine ; Demography ; Female ; Humans ; Male ; Middle Aged ; Nutrition Surveys ; Prevalence ; Republic of Korea/epidemiology ; Sodium, Dietary/*urine ; Stomach Neoplasms/*epidemiology/pathology ; Urine Specimen Collection

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Urinary Sodium Excretion Has Positive Correlation with Activation of Urinary Renin Angiotensin System and Reactive Oxygen Species in Hypertensive Chronic Kidney Disease.

Shin Young AHN ; Sejoong KIM ; Dong Ki KIM ; Jung Hwan PARK ; Sung Joon SHIN ; Sang Ho LEE ; Bum Soon CHOI ; Chun Soo LIM ; Suhnggwon KIM ; Ho Jun CHIN

Journal of Korean Medical Science.2014;29(Suppl 2):S123-S130. doi:10.3346/jkms.2014.29.S2.S123

It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with > or =200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20-0.33) pM/mg cr in patients with > or =200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation.
Adult ; Aged ; Angiotensinogen/urine ; Chemokine CCL2/urine ; Creatine/urine ; Demography ; Female ; Follow-Up Studies ; Humans ; Hypertension/complications ; Male ; Malondialdehyde/urine ; Middle Aged ; Reactive Oxygen Species/*metabolism ; Renal Insufficiency, Chronic/complications/*pathology ; Renin-Angiotensin System/*physiology ; Sodium, Dietary/*urine ; Urine Specimen Collection

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Analysis of Correlation between 24-Hour Urinary Sodium and the Degree of Blood Pressure Control in Patients with Chronic Kidney Disease and Non-Chronic Kidney Disease.

Ho Seok KOO ; Yong Chul KIM ; Shin Young AHN ; Se Won OH ; Suhnggwon KIM ; Ho Jun CHIN

Journal of Korean Medical Science.2014;29(Suppl 2):S117-S122. doi:10.3346/jkms.2014.29.S2.S117

We investigated the association between 24-hr urinary sodium (24UNA) and adequacy of blood pressure (BP) control in patients with chronic kidney disease (CKD) and nonCKD. All data were collected retrospectively by accessing the electrical medical records in patients with 24-hr urine collection and serum creatinine. Enrolled 400 subjects were subgrouped by the amount of 24UNA, or CKD stage. The appropriate BP was defined as BP < 130/80 mmHg for subjects with proteinuria, and BP < 140/90 mmHg for subjects without proteinuria. The mean level of 24UNA was 166+/-76 mEq/day. The 24UNA group was an independently related factor to diastolic BP as a continuous variable. The rate of appropriate BP control in patients with proteinuria was highest in 24UNA <100 mEq/L (P=0.012). The odds to fail achievement of BP target in subjects with 24UNA> or =90 mEq/day was 2.441 (1.249-4.772, P=0.009) higher than that of 24UNA <90 mEq/day among participants with proteinuria. There was difference in the amount of 24UNA between CKD and non-CKD except each stage of CKD group. In conclusion, salt intake estimated by 24-hr urine sodium excretion is a risk factor to achieve appropriate BP control.
Adult ; Aged ; Algorithms ; Blood Pressure/*physiology ; Creatine/blood ; Demography ; Female ; Humans ; Hypertension/complications ; Male ; Middle Aged ; Odds Ratio ; Proteinuria/complications ; Renal Insufficiency, Chronic/complications/*pathology ; Retrospective Studies ; Risk Factors ; Severity of Illness Index ; Sodium, Dietary/*urine ; Urine Specimen Collection

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Estimated 24-Hour Urine Sodium Excretion Is Correlated with Blood Pressure in Korean Population: 2009-2011 Korean National Health and Nutritional Examination Survey.

Jieun OH ; Jeonghwan LEE ; Ho Seok KOO ; Suhnggwon KIM ; Ho Jun CHIN

Journal of Korean Medical Science.2014;29(Suppl 2):S109-S116. doi:10.3346/jkms.2014.29.S2.S109

No large-scale studies have investigated the association between salt intake and hypertension in Korean population. To investigate the relationship of blood pressure to salt consumption, we analyzed data from 19,476 participants in the 2009-2011 Korean National Health and Nutritional Examination Survey (KNHANES). Urinary sodium excretion over 24-hr (24HUNa) was estimated from spot urine tests using Tanaka's equation. The study subjects were stratified into hypertensive and normotensive groups. Hypertensive participants (n=6,552, 33.6%) had higher estimated 24HUNa, 150.4+/-38.8 mEq/day, than normotensive participants, 140.5+/-34.6 mEq/day (P<0.001). The association between 24HUNa and blood pressure outcomes was not affected by adjustment for other risk factors for hypertension (odds ratio 0.001; 95% confidence interval 0.001-0.003; P<0.001). Increases in 24HUNa of 100 mEq/day were associated with a 6.1+/-0.3/2.9+/-0.2 mmHg increase in systolic/diastolic blood pressure in all participants. This effect was stronger in hypertensive participants (increase of 8.1+/-0.5/3.4+/-0.3 mmHg per 100 mEq/day) and smaller in normotensive participants (2.9+/-0.3/1.3+/-0.2 mmHg). These results support recommendations for low salt intake in Korean population to prevent and control adverse blood pressure levels.
Adult ; Algorithms ; Asian Continental Ancestry Group ; Blood Pressure/*physiology ; Demography ; Female ; Humans ; Hypertension/epidemiology/*urine ; Logistic Models ; Male ; Middle Aged ; Nutrition Surveys ; Prevalence ; Republic of Korea/epidemiology ; Risk Factors ; Sodium, Dietary/*urine ; Urine Specimen Collection

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A Higher Salt Intake Leads to a Lower Rate of Adequate Blood Pressure Control.

Jeonghwan LEE ; Hajeong LEE ; Kiwon KIM ; Jung Hwan PARK ; Suhnggwon KIM ; Jieun OH

Journal of Korean Medical Science.2014;29(Suppl 2):S103-S108. doi:10.3346/jkms.2014.29.S2.S103

The relationship between salt intake and adequate blood pressure control is not well investigated in Korea populations, especially in patients with cardiovascular disease. This cross-sectional study enrolled 19,083 subjects who participated in the Korea National Health and Nutrition Examination Survey conducted from 2009-2011. The amount of salt intake was estimated using the Tanaka equations based on spot urine samples. Comparing patients with and without cardiovascular disease, systolic blood pressure (129.1+/-18.1 mmHg vs. 120.0+/-18.1 mmHg, P<0.001) and the amount of urinary sodium excretion (149.4+/-37.5 mM/day vs. 144.1+/-36.2 mM/day, P<0.001) were higher in patients with cardiovascular diseases. Among patients with cardiovascular disease, the high blood pressure group showed an increased amount of urinary sodium excretion compared to the normal blood pressure group (155.5+/-38.2 vs. 146.6+/-36.9 mM/day, P<0.001). The odds ratio (OR) of high blood pressure was higher (OR, 1.825; 95% CI, 1.187-2.807; P-for-trend 0.003, highest quartile of urinary sodium excretion vs. lowest quartile) in patients with cardiovascular disease. A higher amount of urinary sodium excretion was associated with a lower rate of adequate blood pressure control in Korean population, especially with cardiovascular disease.
Adult ; Aged ; Algorithms ; Blood Pressure/*physiology ; Cardiovascular Diseases/complications/*pathology ; Cross-Sectional Studies ; Demography ; Female ; Humans ; Hypertension/complications ; Male ; Middle Aged ; Nutrition Surveys ; Odds Ratio ; Sodium, Dietary/*urine

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Estimating 24-Hour Urine Sodium Level with Spot Urine Sodium and Creatinine.

Ho Seok KOO ; Yong Chul KIM ; Shin Young AHN ; Se Won OH ; Suhnggwon KIM ; Ho Jun CHIN ; Jung Hwan PARK

Journal of Korean Medical Science.2014;29(Suppl 2):S97-S102. doi:10.3346/jkms.2014.29.S2.S97

The 24-hr urine sodium excretion level was estimated based on the spot urine sodium, and the efficacy of the formula was validated to determine the status of low salt intake <100 mEq Na/day. The 24-hr urine samples were collected from 400 patients. The 24-hr urine creatinine level was estimated with the use of three formulas: a newly derived Korean equation (E24UCR_K), and Tanaka (E24UCR_T) and Cockcroft-Gault (E24UCR_CG) equations. The correlation coefficients between the estimated and measured 24-hr urine creatinine for these three equations were 0.863, 0.846, and 0.896, respectively (All P<0.001). After estimating the 24-hr urine sodium levels, the correlation coefficients between the estimated and measured 24-hr urine sodium levels were 0.466, 0.490, and 0.516, respectively (All P<0.001). The sensitivity of three formulas to estimate the measured 24-hr urine sodium> or =100 mEq/day using the estimated amount> or =100 mEq/day was 84.3%, 87.6%, and 84.8%, respectively. In conclusion, the three equations used to estimate the 24-hr urine sodium content were useful to determine the status of low salt intake.
Adult ; Aged ; Algorithms ; Area Under Curve ; Creatinine/*urine ; Demography ; Female ; Glomerular Filtration Rate ; Humans ; Male ; Middle Aged ; ROC Curve ; Sodium, Dietary/*urine ; Urine Specimen Collection

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Not Salt Taste Perception but Self-Reported Salt Eating Habit Predicts Actual Salt Intake.

Hajeong LEE ; Hyun Jeong CHO ; Eunjin BAE ; Yong Chul KIM ; Suhnggwon KIM ; Ho Jun CHIN

Journal of Korean Medical Science.2014;29(Suppl 2):S91-S96. doi:10.3346/jkms.2014.29.S2.S91

Excessive dietary salt intake is related to cardiovascular morbidity and mortality. Although dietary salt restriction is essential, it is difficult to achieve because of salt palatability. However, the association between salt perception or salt eating habit and actual salt intake remains uncertain. In this study, we recruited 74 healthy young individuals. We investigated their salt-eating habits by questionnaire and salt taste threshold through a rating scale that used serial dilution of a sodium chloride solution. Predicted 24-hr urinary salt excretions using Kawasaki's and Tanaka's equations estimated dietary salt intake. Participants' mean age was 35 yr, and 59.5% were male. Salt sense threshold did not show any relationship with actual salt intake and a salt-eating habit. However, those eating "salty" foods showed higher blood pressure (P for trend=0.048) and higher body mass index (BMI; P for trend=0.043). Moreover, a salty eating habit was a significant predictor for actual salt intake (regression coefficient [beta] for Kawasaki's equation 1.35, 95% confidence interval [CI] 10-2.69, P=0.048; beta for Tanaka's equation 0.66, 95% CI 0.01-1.31, P=0.047). In conclusion, a self-reported salt-eating habit, not salt taste threshold predicts actual salt intake.
Adult ; Algorithms ; Blood Pressure ; Body Mass Index ; Demography ; Female ; Habits ; Humans ; Linear Models ; Male ; Questionnaires ; Self Report ; Sodium Chloride, Dietary/*urine ; Taste Perception ; Taste Threshold ; Urine Specimen Collection

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