Yung-Ho Hsu

Taipei Medical University, T’ai-pei, Taipei, Taiwan

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Publications (34)103.31 Total impact

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    ABSTRACT: The safety and efficacy of continuous infusion vs bolus injection of intravenous loop diuretics to treat acute decompensated heart failure were debated. Our aim is to compare the administration routes of diuretics in hospitalized patients with acute decompensated heart failure. A systematic review and meta-analysis of randomized controlled trials was performed to evaluate the effects of continuous infusion vs bolus administration of loop diuretics in patients with acute decompensated heart failure. The primary end points were urine outputs, body weight loss, all causes of mortality, and death from cardiovascular causes. Secondary end points were electrolyte imbalance, change in creatinine levels, tinnitus or hearing loss, and days of hospitalization. Ten randomized controlled trials with 518 patients were identified. Continuous infusion of diuretics was associated with a significantly greater weight loss (weighted mean difference, 0.78; 95% confidence interval, 0.03-1.54) compared with bolus injection. Urine output, the incidence of electrolyte imbalance, change in creatinine level, length of hospitalization, the incidence of ototoxicity, cardiac mortality, and all-cause mortality showed no significant differences between the 2 groups. Meta-analysis of the existing limited studies did not confirm any significant differences in the safety and efficacy with continuous administration of loop diuretic, compared with bolus injection in patients with acute decompensated heart failure.
    Journal of critical care 02/2014; 29(1):2-9. · 2.13 Impact Factor
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) occurs in stressed tubular epithelial cells, contributing to renal fibrosis. Initial mechanisms promoting EMT are unknown. Pressure force is an important mechanism contributing to the induction and progression of renal fibrogenesis in ureteric obstruction. In our study of cultured rat renal tubular cells (NRK-52E) under 60 mmHg of pressure, we found that the epithelial marker E-cadherin decreased and mesenchymal markers, e.g., α-smooth muscle actin, fibronectin and Snail, increased. Pressure also induced the expression of connective tissue growth factor and transforming growth factor-β. MicroRNA array assays showed that pressure reduced miR-328 at the initial stage of pressurization. We identified a potential target sequence of miR-328 in rat CD44 3'-untranslated regions. In contrast with the miR-328 expression, CD44 expression was up-regulated at the initial pressurization stage. We also found that miR-328 expression decreased and CD44 increased in ureteric obstruction kidneys in the animal study. CD44 siRNA transfection significantly increased E-cadherin expression and inhibited pressure-induced EMT. Both hyaluronan binding peptide pep-1 and osteopontin neutralizing antibody inhibited pressure-induced EMT. Our results suggest that miR-328-mediated CD44 transient upregulation is an important trigger of the pressure-induced EMT in renal fibrosis.
    PLoS ONE 01/2014; 9(6):e99802. · 3.53 Impact Factor
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    ABSTRACT: Zhibai Dihuang Wan (ZDW) is an ancient traditional Chinese medicine composed of eight herbal ingredients and has been used to treat chronic kidney inflammation and diabetes for thousands of years. Nonetheless, the influence of ZDW on acute kidney injury is still unknown. We intended to identify the influence of ZDW on cell growth and gentamicin-induced apoptotic injury in renal tubular cells. We extracted ZDW with artificial intestinal fluid and treated rat renal tubular cells (NRK-52E) with various concentrations of the ZDW extraction. Cell proliferation and gentamicin-induced apoptosis of NRK-52E cells were evaluated using real-time proliferation monitoring and annexin V staining, respectively. Western blotting was used to evaluate the levels of Bcl-2 and caspase-3 expression. The effect of ZDW on gentamicin-induced kidney injury was also monitored in mice using the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assay, and the measurement of serum creatinine and blood urea nitrogen. We found that 30μg/ml of ZDW promoted cell proliferation of the rat renal tubular cells. ZDW also expressed a dose-dependent protective effect against gentamicin-induced apoptosis in the cells. Pretreatment with 3μg/ml or 30μg/ml of ZDW maximally increased Bcl-2 and decreased cleaved caspase-3 in the gentamicin-treated NRK-52E cells. Among the herbal ingredients of ZDW, only Phellodendron amurense Rupr., bark (Cortex Phellodendri), and Anemarrhena asphodeloides Bunge, rhizome inhibited both the gentamicin-induced Bcl-2 decrease and cleaved caspase-3 increase. Phellodendron amurense Rupr., bark and Anemarrhena asphodeloides Bunge, rhizome also inhibited gentamicin-induced apoptosis at particular concentrations; however, these two ingredients were less effective than ZDW. In the mouse model of gentamicin-induced nephropathy, the ZDW treatment significantly reduced apoptotic cells in the renal cortex and improved renal function. Our results suggest that ZDW at adequate doses attenuates gentamicin-induced apoptotic injury in renal tubular cells and also protects kidneys from gentamicin-induced injury in mice.
    Journal of ethnopharmacology 11/2013; · 2.32 Impact Factor
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    ABSTRACT: Urotensin II (UII) is a cyclic vasoactive peptide which is mainly expressed in kidneys. Although elevated plasma UII levels are associated with renal impairment, the influence of UII on renal injury is unclear. In this study, we monitored the influence of UII on gentamicin-induced apoptosis in rat tubular cells (NRK-52E). We found that UII significantly reduced gentamicin-induced apoptosis and apoptotic signals. Blocking endogenous UII secretion caused cells to be more susceptible to gentamicin. In gentamicin-treated mice, UII also expressed protective effect on renal tubular cells. UII was also found to induce prostacyclin (PGI2) production, which caused peroxisomal proliferator-activated receptor α (PPARα) activation as revealed by both PGI2 synthase siRNA transfection and piroxicam treatment. Blockage of PPARα by siRNA transfection inhibited UII-induced Akt phosphorylation and the antiapoptotic effect of UII. Our results suggest that UII can protect renal tubular cells from gentamicin-induced apoptosis through PGI2-mediated PPARα and Akt activation.
    Molecular and Cellular Endocrinology 08/2013; · 4.04 Impact Factor
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    ABSTRACT: BACKGROUND: N-Acetylcysteine (NAC) is reported to have potential for preventing of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography. However, the effectiveness of NAC in preventing CIN in patients undergoing contrast-enhanced computed tomography (CT) is still controversial. We conducted a meta-analysis of relevant randomized controlled trials (RCTs) to further examine this issue. METHODS: RCTs were identified by computerized searching in PubMed, EMBASE, SCOPUS, and Cochrane databases. Two reviewers independently assessed the methodological quality of each study. A meta-analysis was performed to evaluate the effectiveness of NAC in preventing CIN in patients undergoing CT. The primary outcome was the incidence of contrast-induced nephropathy, and the requirement for dialysis. The secondary outcome was the change of serum creatinine. RESULTS: Six randomized controlled trials were identified with a total of 496 patients meeting the criteria for this study. Prophylactic administration of NAC in patients with serum creatinine above 1.2 mg/dL undergoing contrast-enhanced CT, along with hydration, reduced the risk of CIN (relative risk 0.20; 95 % confidence interval: 0.07-0.57). Requirement for dialysis was not significantly different between the NAC group and the control group. CONCLUSIONS: This review provides evidence of the efficacy of NAC in preventing the incidence of CIN and recommends that NAC be more widely used in high-risk patients undergoing contrast-enhanced CT. On the basis of the evidence reviewed, further research involving large RCTs may be warranted.
    International Urology and Nephrology 01/2013; · 1.33 Impact Factor
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    ABSTRACT: Statins are reported to alleviate renal fibrosis in animal models with ureteral obstruction. However, the molecular mechanism of this antifibrotic effect is still unclear. Pressure force is an important mechanism contributing to induction and progression of tubulointerstitial fibrogenesis in ureteric obstruction. In this study, we investigated the influence of rosuvastatin on pressure-induced fibrotic responses in rat renal tubular cells (NRK-52E). We established an in vitro pressure culture system to study pressure-induced fibrotic responses in NRK-52E cells. When NRK-52E cells were cultured in the pressure culture system, 60mmHg of pressure induced the expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)-β, fibronectin, Smad3, and phospho-Smad3. Rosuvastatin significantly reduced these pressure-induced fibrotic responses at concentrations above 10μM. Rosuvastatin also reduced the TGF-β-induced expression of fibronectin and CTGF in NRK-52E cells. Pretreatment with rosuvastatin significantly induced prostacyclin (PGI(2)) generation, but reduced pressure-induced prostaglandin E(2) (PGE(2)). PGI(2) synthase small interfering RNA (siRNA) transfection significantly inhibited rosuvastatin-induced peroxisome proliferator-activated receptor α activation. The blockage of peroxisome proliferator-activated receptor α by siRNA transfection reduced the inhibitory effect of rosuvastatin on pressure-induced fibrotic responses. N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398), a specific inhibitor of cyclooxygenase-2, diminished pressure-induced PGE(2) generation, and also reduced pressure-induced fibrotic responses. Additionally, PGE(2) decreased the antifibrotic effect of rosuvastatin. In conclusion, rosuvastatin reduces pressure-induced fibrotic responses in renal tubular cells by enhancing the PGI(2)- peroxisome proliferator-activated receptor α pathway and reducing PGE(2) generation.
    European journal of pharmacology 12/2012; · 2.59 Impact Factor
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    ABSTRACT: PURPOSE: We evaluate the risk factors for nocturia in patients with chronic kidney disease, and determine whether the metabolic syndrome and its components aggravate nocturia in these patients. MATERIALS AND METHODS: We enrolled patients with chronic kidney disease who had regular followup at nephrology clinics, and excluded from study those patients undergoing dialysis, and those with neurogenic bladder or active urinary tract infection. Patients were asked to complete a questionnaire including medical history, clinical parameters and times of nocturnal voids in the last month. Laboratory parameters were checked when the questionnaire was completed. Clinically significant nocturia was defined as voiding 2 or more times per night. The metabolic syndrome was defined according to the ATP III (National Cholesterol Education Program Adult Treatment Panel III) guidelines. Chronic kidney disease was divided into 5 stages (based on National Kidney Foundation guidelines). Multivariate logistic regression was used to evaluate the risk factors for clinically significant nocturia. RESULTS: A total of 202 men and 234 women were eligible for analysis (mean age 68.4 years). The prevalence rate of clinically significant nocturia in patients with chronic kidney disease was 64.0%. Statistically significant risk factors for clinically significant nocturia were patient age (OR 1.02, 95% CI 1.003-1.04) and chronic kidney disease stage (OR 1.47, 95% CI 1.19-1.81) but not gender. Although 53.9% of our patients with chronic kidney disease had the metabolic syndrome, the metabolic syndrome (adjusted OR 0.96, 95% CI 0.64-1.44) and its components had no significant correlations with clinically significant nocturia. CONCLUSIONS: Clinically significant nocturia is prevalent in patients with chronic kidney disease, and the severity increased with chronic kidney disease stage and patient age. Contrary to previous reports, the metabolic syndrome did not increase the risk of clinically significant nocturia in patients with chronic kidney disease.
    The Journal of urology 10/2012; · 3.75 Impact Factor
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    ABSTRACT: Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24h, but significantly increased apoptosis at 48 h. Long-term treatment of leptin decreased Bcl-x(L) expression and increased caspase activity in gentamicin-treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E(2) (PGE(2)), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE(2) augmentation and the pro-apoptotic effects of leptin. The addition of PGE(2) recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2-mediated PGE(2) augmentation in renal tubular cells, and then increases these cells' susceptibility to gentamicin-induced apoptosis.
    European journal of pharmacology 06/2012; 689(1-3):65-71. · 2.59 Impact Factor
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    ABSTRACT: Immune system dysregulation is associated with end-stage renal disease. Although decreased cellular immunity increases susceptibility to herpes zoster, the risk of herpes zoster in patients with earlier stages of chronic kidney disease (CKD) is unclear. A matched-cohort study. Data from the Taiwan Longitudinal Health Insurance Database (LHID) for 2004-2006 were analyzed. The study cohort included patients 18 years or older given a diagnosis of CKD (excluding patients treated by dialysis or transplant) in 2004-2005 (n = 13,321). The comparison cohort (n = 66,605) included 5 randomly selected age- and sex-matched controls for each patient in the study cohort. CKD. Incident cases of CKD were identified using the Taiwan LHID. CKD was ascertained from International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Herpes zoster, ascertained from ICD-9-CM codes. All participants were followed up from the date of cohort entry until they developed herpes zoster or the end of 2006. Cox proportional hazard regressions were performed to compare the hazard rates of herpes zoster in the CKD cohort and the age- and sex-matched comparison cohort. We identified 13,321 patients with a diagnosis of CKD who matched the inclusion criteria. 1,602 patients developed herpes zoster during the study period, of whom 353 were from the CKD cohort and 1,249 were from the comparison cohort. After adjusting for potential confounding factors, CKD was associated independently with greater risk of herpes zoster (HR, 1.60; 95% CI, 1.41-1.81). Some patients with CKD or herpes zoster may have chosen not to seek medical care. Misclassification of CKD due to use of diagnostic codes also is a limitation. This population-based cohort study indicated that patients with CKD are at increased risk of herpes zoster compared with the general population.
    American Journal of Kidney Diseases 05/2012; 60(4):548-52. · 5.29 Impact Factor
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    ABSTRACT: Dysregulation of canonical Wnt signaling is thought to play a role in colon carcinogenesis. β-Catenin, a key mediator of the pathway, is stabilized upon Wnt activation and accumulates in the nucleus, where it can interact with the transcription factor T cell factor (TCF) to transactivate gene expression. Normal colonic epithelia express a truncated TCF-1 form, called dnTCF-1, that lacks the critical β-catenin-binding domain and behaves as a transcriptional suppressor. How the cell maintains a balance between the two forms of TCF-1 is unclear. Here, we show that ERM-binding phosphoprotein 50 (EBP50) modulates the interaction between β-catenin and TCF-1. We observed EBP50 localization to the nucleus of human colorectal carcinoma cell lines at low cell culture densities and human primary colorectal tumors that manifested a poor clinical outcome. In contrast, EBP50 was primarily membranous in confluent cell lines. Aberrantly located EBP50 stabilized conventional β-catenin/TCF-1 complexes and connected β-catenin to dnTCF-1 to form a ternary molecular complex that enhanced Wnt/β-catenin signaling events, including the transcription of downstream oncogenes such as c-Myc and cyclin D1. Genome-wide analysis of the EBP50 occupancy pattern revealed consensus binding motifs bearing similarity to Wnt-responsive element. Conventional chromatin immunoprecipitation assays confirmed that EBP50 bound to genomic regions highly enriched with TCF/LEF binding motifs. Knockdown of EBP50 in human colorectal carcinoma cell lines compromised cell cycle progression, anchorage-independent growth, and tumorigenesis in nude mice. We therefore suggest that nuclear EBP50 facilitates colon tumorigenesis by modulating the interaction between β-catenin and TCF-1.
    The Journal of clinical investigation 04/2012; 122(5):1881-94. · 15.39 Impact Factor
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    ABSTRACT: Anticoagulation of the extracorporeal circuit is required in continuous renal replacement therapy (CRRT). Heparin is the classic choice for anticoagulation, although it may increase the risk of bleeding. Regional citrate anticoagulation reduces the risk of bleeding, but may cause hypocalcemia and metabolic disturbances. Systematic review and meta-analysis of randomized controlled trials (RCTs). Patients admitted to the intensive care unit with acute kidney injury that required CRRT. RCTs regardless of publication status or language. Regional citrate versus heparin anticoagulation in CRRT. The primary outcomes were circuit survival time, the occurrence of major bleeding defined as a site of gross bleeding with a decrease in blood pressure or requiring transfusion of 2 or more units of red blood cells, metabolic alkalosis, hypocalcemia, and thrombocytopenia. The secondary outcome was cost. 6 RCTs with 488 patients were identified. Citrate anticoagulation was associated with a significant decrease in bleeding (RR, 0.34; 95% CI, 0.17-0.65). Circuit survival time, the incidence of metabolic alkalosis, and thrombocytopenia showed no significant difference between groups. Hypocalcemia was more common in patients receiving citrate, although no clinical adverse event was reported in the included studies. Significant heterogeneity in the primary outcome. The efficacy of citrate and heparin anticoagulation for CRRT was similar. However, citrate anticoagulation decreased the risk of bleeding with no significant increase in the incidence of metabolic alkalosis. We recommend citrate as an anticoagulation agent in patients who require CRRT but are at high risk of bleeding.
    American Journal of Kidney Diseases 01/2012; 59(6):810-8. · 5.29 Impact Factor
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    ABSTRACT: Many studies suggest that far-infrared (FIR) therapy can reduce the frequency of some vascular-related diseases. The non-thermal effect of FIR was recently found to play a role in the long-term protective effect on vascular function, but its molecular mechanism is still unknown. In the present study, we evaluated the biological effect of FIR on vascular endothelial growth factor (VEGF)-induced proliferation in human umbilical vein endothelial cells (HUVECs). We found that FIR ranging 3∼10 µm significantly inhibited VEGF-induced proliferation in HUVECs. According to intensity and time course analyses, the inhibitory effect of FIR peaked at an effective intensity of 0.13 mW/cm(2) at 30 min. On the other hand, a thermal effect did not inhibit VEGF-induced proliferation in HUVECs. FIR exposure also inhibited the VEGF-induced phosphorylation of extracellular signal-regulated kinases in HUVECs. FIR exposure further induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO generation in VEGF-treated HUVECs. Both VEGF-induced NO and reactive oxygen species generation was involved in the inhibitory effect of FIR. Nitrotyrosine formation significantly increased in HUVECs treated with VEGF and FIR together. Inhibition of phosphoinositide 3-kinase (PI3K) by wortmannin abolished the FIR-induced phosphorylation of eNOS and Akt in HUVECs. FIR exposure upregulated the expression of PI3K p85 at the transcriptional level. We further found that FIR exposure induced the nuclear translocation of promyelocytic leukemia zinc finger protein (PLZF) in HUVECs. This induction was independent of a thermal effect. The small interfering RNA transfection of PLZF blocked FIR-increased PI3K levels and the inhibitory effect of FIR. These data suggest that FIR induces the nuclear translocation of PLZF which inhibits VEGF-induced proliferation in HUVECs.
    PLoS ONE 01/2012; 7(1):e30674. · 3.53 Impact Factor
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    ABSTRACT: Secondary hyperparathyroidism (SHPT) is a common complication in chronic renal disease. Osteoprotegerin (OPG), an extracellular cytokine receptor secreted by osteoblasts, can promote bone formation by inhibiting the function of osteoclasts. Hemodialysis (HD) patients have elevated serum OPG levels. OPG secretion can be suppressed with high parathyroid hormone (PTH) levels. HD patients with refractory SHPT can benefit from parathyroidectomy (PTX) treatment, but the changes of serum OPG, bone turnover markers and bone mineral density (BMD) following PTX in HD patients remain unclear. In this study, patients on maintenance HD who received PTX for refractory SHPT (n = 28) were prospectively followed for 1 year. Serum intact PTH (iPTH), alkaline phosphatase (Alk-P), and OPG were measured serially; BMD was measured pre-PTX and at 1 year after PTX. After PTX, serum iPTH levels reduced profoundly. Serum Alk-P levels increased rapidly, peaking at 2 weeks post-PTX, while serum OPG levels gradually increased at 2 weeks after PTX and peaked at 2 months. BMD improved in both femoral neck (FN; cancellous and cortical bone) and lumbar spine (LS; cancellous bone). Higher baseline iPTH levels were associated with greater FN and LS BMD improvements at one year after PTX. The increment of serum OPG was correlated with the increase in LS BMD, implying that inhibition of osteoclastic bone resorption may improve BMD within the first year after PTX. These findings suggest that PTX removes the suppressive effects of high PTH on OPG secretion, resulting in the increased serum OPG levels that may contribute to BMD improvement.
    The Tohoku Journal of Experimental Medicine 01/2012; 226(1):19-27. · 1.37 Impact Factor
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    ABSTRACT: Leptin, a circulating hormone secreted mainly from adipose tissues, possesses protective effects on many cell types. Serum leptin concentration increases in patients with chronic renal failure and those undergoing maintenance dialysis. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. In the present study, we intended to investigate the influence of leptin on apoptotic pathways and its mechanism in rat renal tubular cells treated with gentamicin. By using Annexin V-FITC/propidium iodide double staining, we found that leptin expressed a dose-dependent protective effect against gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) within 24h. Pretreatment of the cells with 50 or 100 ng/ml of leptin induced Bcl-2 and Bcl-x(L), increased the phosphorylation of Bad, and decreased the cleaved caspase-3 and caspase-9 in gentamicin-treated NRK-52E cells. Leptin also suppressed the activation of the transcription factor NF-κB and upregulated Akt activation in gentamicin-treated NRK-52E cells. We found that leptin activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway as demonstrated by the suppression of the anti-apoptotic effect of leptin by wortmannin. The treatment of wortmannin suppressed the leptin-induced phospho-Akt, Bcl-2, phospho-Bad as well as Bcl-x(L), and recovered the leptin-reduced cleaved caspase-3 and caspase-9. Based on our results, we suggested that leptin can attenuate gentamicin-induced apoptotic injury in rat renal tubular cells through PI3K/Akt signaling pathway.
    European journal of pharmacology 02/2011; 658(2-3):213-8. · 2.59 Impact Factor
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    ABSTRACT: Vascular calcification is common in ESRD patients and is important in increasing mortality from cardiovascular complications in these patients. Hyperphosphatemia related to chronic kidney disease is increasingly known as major stimulus for vascular calcification. Hyperphosphatemia and vascular calcification become popular discussion among nephrologist environment more than five decades, and many researches have been evolved. Risk factors for calcification are nowadays focused for the therapeutic prevention of vascular calcification with the hope of reducing cardiovascular complications.
    International journal of nephrology. 01/2011; 2011:939613.
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    ABSTRACT: Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages.
    American Journal Of Pathology 06/2010; 176(6):3050-61. · 4.60 Impact Factor
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    ABSTRACT: L-carnitine is synthesized mainly in the liver and kidneys from lysine and methionine from dietary sources. Many reports have shown that L-carnitine can protect certain cells against the toxicity of several anticancer and toxic agents, although the detailed mechanism is poorly understood. In this study, we investigated the protective effect of L-carnitine and its molecular mechanism in renal tubular cells undergoing gentamicin-induced apoptosis. Rat tubular cell line (NRK-52E) and mice were used as the model system. Gentamicin-induced apoptosis in renal tubular cells was examined using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling. We introduced short interfering RNA transfection and gene-deficient mice to investigate the protective mechanism of L-carnitine. We found that L-carnitine inhibited gentamicin-induced reactive oxygen species generation and correlative apoptotic pathways, resulting in the protection of NRK-52E cells from gentamicin-induced apoptosis. The treatment of L-carnitine also lessened gentamicin-induced renal tubular cell apoptosis in mice. L-carnitine was found to increase the prostacyclin (PGI(2)) generation in NRK-52E cells. The siRNA transfection for PGI(2) synthase significantly reduced L-carnitine-induced PGI(2) and L-carnitine's protective effect. We found that the activity of the potential PGI(2) nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), was elevated by L-carnitine treatment. The siRNA-mediated blockage of PPARalpha considerably reduced the anti-apoptotic effect of L-carnitine. In PPARalpha-deficient mice, L-carnitine treatment also lost the inhibitory effect on gentamicin-induced apoptosis in kidneys. Based on these findings, we suggest that L-carnitine protects renal tubular cells from gentamicin-induced apoptosis through PGI(2)-mediated PPARalpha activation.
    Nephrology Dialysis Transplantation 07/2009; 24(10):3042-9. · 3.37 Impact Factor
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    ABSTRACT: Urotensin-II (UII) is a potent vasoactive peptide that has been implicated in cardiac fibrosis and renal diseases. However, the role played by UII in renal tissues is largely unknown. In this study, we investigated the effects of human UII (hUII) on rat renal proximal tubular cells of the NRK-52E line and the role of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) in the hUII-induced transactivation of the epidermal growth factor receptor (EGFR). Exposure to hUII at low concentrations significantly induced proliferation in NRK-52E cells; this effect was inhibited by treatment with an ERK1/2 inhibitor (PD98059). UII treatment increased the phosphorylation of EGFR and induced the generation of reactive oxygen species (ROS). Treatment of the ROS scavenger N-acetyl-cysteine (NAC) inhibited EGFR transactivation and ERK phosphorylation induced by hUII. SHP-2 was found to interact with EGFR and be transiently oxidized following the hUII treatment. In SHP-2 knockdown cells, UII-induced phosphorylation of EGFR was less influenced by NAC, and significantly suppressed by heparin binding (HB)-EGF neutralizing antibody. Our data suggest that the ROS-mediated oxidation of SHP-2 is essential for the hUII-induced mitogenic pathway in NRK-52E cells.
    Growth factors (Chur, Switzerland) 04/2009; 27(3):155-62. · 2.47 Impact Factor
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    ABSTRACT: We have demonstrated that uraemic neutrophils that exhibit a low intracellular pH (pHi) display enhanced phagocytosis. However, the underlying cellular mechanism is unclear. We used neutrophils from three groups of haemodialysis (HD) patients before dialysis (Groups A, B and C) and also from age- and sex-matched healthy individuals to determine pHi, phagocytosis and expression of CD11b, CD18, CD14 and toll-like receptors (TLR)-2 and TLR-4. The patients were categorized based on three consecutive monthly pre-dialysis plasma bicarbonate concentrations(P(HCO3)) and pH values; Groups A, B and C had a constant pre-dialysis P(HCO3) of </=21, 21-26 and >/=26 mmol/L (mEq/L), respectively. We also studied the effects induced by the correction of metabolic acidosis and monoclonal antibodies (mAbs) against CD11b/CD18 on neutrophils in Group A. Furthermore, we investigated the effect of intracellular acidification on uraemic neutrophils ex vivo. We observed that the neutrophils in Group A exhibited significantly increased phagocytosis and expression of CD11b/CD18 compared with those in Groups B and C. Additionally, our ex vivo studies demonstrated that the mAbs against CD11b/CD18 partially blocked the enhancement of neutrophil phagocytosis in Group A. Moreover, the pHi of uraemic neutrophils is inversely correlated with phagocytosis and expression of CD11b/CD18. HD patients with a low P(HCO3) exhibited low neutrophil pHi that in turn increased the expression of CD11b/CD18 compared with neutrophils with a normal or high pHi. This increased expression of CD11b/CD18 on the uraemic neutrophils may contribute to the pHi-mediated phagocytosis.
    Nephrology Dialysis Transplantation 06/2008; 23(5):1642-9. · 3.37 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a transcription factor and has been reported to inhibit cisplatin-mediated proximal tubule cell death. In addition, doxorubicin (Adriamycin)-induced nephrosis in rats is a commonly used experimental model for pharmacological studies of human chronic renal diseases. In this study, we investigated the protective effect of PPAR-alpha on doxorubicin-induced apoptosis and its detailed mechanism in NRK-52E cells and animal models. The mRNA level of PPAR-alpha was found to be reduced by doxorubicin treatment in NRK-52E cells. PPAR-alpha overexpression in NRK-52E cells significantly inhibited doxorubicin-induced apoptosis and the quantity of cleaved caspase-3. Endogenous prostacyclin (PGI(2)) augmentation, which has been reported to protect NRK-52E cells from doxorubicin-induced apoptosis, induced the translocation and activation of PPAR-alpha. The transformation of PPAR-alpha short interfering RNA was applied to silence the PPAR-alpha gene, which abolished the protective effect of PGI(2) augmentation in doxorubicin-treated cells. To confirm the protective role of PPAR-alpha in vivo, PPAR-alpha activator docosahexaenoic acid (DHA) was administered to doxorubicin-treated mice, and it has been shown to significantly reduce the doxorubicin-induced apoptotic cells in renal cortex. However, this protective effect of DHA did not exist in PPAR-alpha-deficient mice. In NRK-52E cells, the overexpression of PPAR-alpha elevated the activity of catalase and superoxide dismutase and inhibited doxorubicin-induced reactive oxygen species (ROS). PPAR-alpha overexpression also inhibited the doxorubicin-induced activity of nuclear factor-kappaB (NF-kappaB), which was associated with the interaction between PPAR-alpha and NF-kappaB p65 subunit as revealed in immunoprecipitation assays. Therefore, PPAR-alpha is capable of inhibiting doxorubicin-induced ROS and NF-kappaB activity and protecting NRK-52E cells from doxorubicin-induced apoptosis.
    Molecular Pharmacology 12/2007; 72(5):1238-45. · 4.41 Impact Factor

Publication Stats

241 Citations
103.31 Total Impact Points

Institutions

  • 2006–2014
    • Taipei Medical University
      • • Division of Nephrology
      • • Department of Internal Medicine
      T’ai-pei, Taipei, Taiwan
  • 2002–2012
    • Wan Fang Hospital
      T’ai-pei, Taipei, Taiwan
  • 2006–2007
    • National Taiwan University Hospital
      • Department of Internal Medicine
      T’ai-pei, Taipei, Taiwan
  • 2003
    • The Chinese University of Hong Kong
      Hong Kong, Hong Kong