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Tainan, Taiwan

Chen J.-Y.,National Cheng Kung University | Chou C.-H.,Tainan Sinlau Hospital | Tsai W.-C.,National Cheng Kung University | Wang M.-C.,National Cheng Kung University | And 4 more authors.
Journal of the American Society of Hypertension | Year: 2012

Nonalcoholic fatty liver disease (NAFLD) is associated with increasing arterial stiffness. We studied the effects of inflammation on different measurements of arterial stiffness in NAFLD. We recruited 80 patients with NAFLD and 40 control subjects. Both compliance index (CI) and stiffness index (SI) were measured. Patients with NAFLD had significantly lower CI (3.8 ± 2.1 vs 4.9 ± 2.9 units; P <.05) and higher SI (8.5 ± 2.4 vs 7.1 ± 1.5 m/s; P <.05) than the controls. Patients with NAFLD were further divided into 2 groups according to the median level of high-sensitivity C-reactive protein (hs-CRP). The CI was significantly lower in patients with NAFLD with high hs-CRP than in those with low hs-CRP (3.2 ± 1.7 vs 4.4 ± 2.5 units; P <.05); however, SI was not statistically different. We further found that waist circumference (odds ratio, 1.06; 95% confidence interval, 1.01-1.13; P <.05) was the only independent factor that predicted low CI (


Chen C.-A.,Tainan Sinlau Hospital | Cheng Y.-C.,Kaohsiung Medical University | Hwang J.-C.,Chi Mei Fundation Hospital | Chang J.-M.,Kaohsiung Medical University | And 2 more authors.
Experimental Biology and Medicine | Year: 2012

Cyclin D1 plays significant roles in cell cycle entry and migration. We have documented that both integrin a3ß1 expressions and the number of podocytes were reduced in focal segmental glomerulosclerosis. We wondered whether integrin- extracellular matrix (ECM) interaction was involved in the regulation of cyclin D1 expression, and the possible signaling pathways in mitogen-stimulating podocytes. Cultured podocytes were divided into serum (mitogens/growth factors)- starved and serum-stimulated groups. Reverse transcription polymerase chain reaction was used to detect cyclin D1 mRNA, and Western blot analysis was used to measure protein concentrations of cyclin D1 and extracellular signalregulated kinase (ERK) activation (p-ERK/ERK). The integrin-ECM interaction was blocked by anti-ß1-integrin monoclonal antibody or RGDS (Arg-Gly-Asp-Ser). The MEK inhibitor, U0126, was used to inhibit ERK activation. The results showed that there was little cyclin D1 protein in serum-starved groups, but it was abundant in serum-stimulated groups. Both cyclin D1 mRNA and protein levels were reduced in serum-stimulated podocytes after blocking integrin-ECM interaction. ERK activation in serum-stimulated podocytes was significantly decreased after blocking integrin-ECM interaction. Cyclin D1 mRNA and protein concentrations in serum-stimulated podocytes were reduced after blocking ERK activation by U0126. We demonstrate that integrin-ECM interaction collaborates with mitogens to activate ERK/mitogen-activated protein kinase pathways which are essential for cyclin D1 expression in podocytes.


Cheng Y.-C.,Kaohsiung Medical University | Chen C.-A.,Tainan Sinlau Hospital | Chang J.-M.,Kaohsiung Municipal Hsiao Kang Hospital | Chen H.-C.,Kaohsiung Medical University
Journal of Biochemistry | Year: 2014

Proteinuria is a major hallmark of glomerular nephropathy and endoplasmic reticulum (ER) stress plays an important role in glomerular nephropathy. The protein levels of integrin-β1 in podocytes are found to be negative correlation with amount of proteinuria. This study investigated whether urinary protein, particularly albumin, induced ER stress that consequently reduced integrin-β1 expression. All experiments were performed using primary cultured rat podocyte. Protein and mRNA expression were measured by western blotting and semiquantified reverse transcriptase polymerase chain reaction. Albumin uptake was found at 1 h after albumin addition. Albumin reduced precursor and mature forms of integrin-β1, but did not change mRNA levels of integrinβ1. Albumin induced reactive oxygen species (ROS) generation and ER stress. Antioxidant (N-acetylcysteine) suppressed albumin-induced ER stress and decrements in precursor and mature forms of integrin-β1. Then, ER stress inhibitors (4-phenylbutyrate and salubrinal) also inhibited albumin-induced decrements in precursor and mature forms of integrin-β1. The potent ER stress inducers (thapsigargin and tunicamycin) directly decreased precursor and mature forms of integrin-β1 and led appearance of unglycosylated core protein of integrin-β1. Our results show that in proteinuric disease, albumin decreases precursor and mature forms of integrin-β1 through ROS-ER stress pathway in podocytes. © The Authors 2015.


Chou C.-H.,Tainan Sinlau Hospital | Tsai W.-C.,National Cheng Kung University | Wang M.-C.,National Cheng Kung University | Ho C.-S.,National Taiwan Sport University | And 4 more authors.
International Heart Journal | Year: 2013

Premature arteriosclerosis may be one of the mechanisms linking pre-diabetes mellitus (pre-DM) and cardiovascular disease. We sought to characterize premature arteriosclerosis in pre-DM using different arterial stiffness indices and to find the independent contributors of this process. We recruited 33 patients without DM, 53 patients with pre-DM, and 34 subjects with DM. Both the compliance index (CI) and stiffness index (SI) were measured. Patients with pre-DM and DM had lower CI (3.8 ± 2.1 versus 5.2 ± 3.0 units; P < 0.05 and 3.6 ± 1.8 versus 5.2 ± 3.0 units; P < 0.05, respectively) and higher SI (8.0 ± 2.0 versus 6.7 ± 1.6 m/s; P < 0.01 and 9.4 ± 2.3 versus 6.7 ± 1.6 m/s; P < 0.001, respectively) than patients without DM. Using multivariate linear regression analysis, age, heart rate, and HOMA index were independent determinants for SI (whole model: R2 = 0.47, P < 0.001), whereas male gender, hsCRP, and HOMA index were independent determinants for CI (whole model: R2 = 0.34, P < 0.01). The HOMA index was an independent determinant for arterial stiffness. Increased insulin resistance may associate with increased arterial stiffness at peripheral arteries in pre-DM patients.


Cheng Y.-C.,Kaohsiung Medical University | Chang J.-M.,Kaohsiung Municipal Hsiao Kang Hospital | Chang J.-M.,Kaohsiung Medical University | Chen C.-A.,Tainan Sinlau Hospital | Chen H.-C.,Kaohsiung Medical University
Experimental Biology and Medicine | Year: 2015

Endoplasmic reticulum stress occurs in a variety of patho-physiological mechanisms and there has been great interest in managing this pathway for the treatment of clinical diseases. Autophagy is closely interconnected with endoplasmic reticulum stress to counteract the possible injurious effects related with the impairment of protein folding. Studies have shown that glomerular podocytes exhibit high rate of autophagy to maintain as terminally differentiated cells. In this study, podocytes were exposed to tunicamycin and thapsigargin to induce endoplasmic reticulum stress. Thapsigargin/tunicamycin treatment induced a significant increase in endoplasmic reticulum stress and of cell death, represented by higher GADD153 and GRP78 expression and propidium iodide flow cytometry, respectively. However, thapsigargin/tunicamycin stimulation also enhanced autophagy development, demonstrated by monodansylcadaverine assay and LC3 conversion. To evaluate the regulatory effects of autophagy on endoplasmic reticulum stress-induced cell death, rapamycin (Rap) or 3-methyladenine (3-MA) was added to enhance or inhibit autophagosome formation. Endoplasmic reticulum stress-induced cell death was decreased at 6 h, but was not reduced at 24 h after Rap+TG or Rap+TM treatment. In contrast, endoplasmic reticulum stress-induced cell death increased at 6 and 24 h after 3-MA+TG or 3-MA+TM treatment. Our study demonstrated that thapsigargin/tunicamycin treatment induced endoplasmic reticulum stress which resulted in podocytes death. Autophagy, which counteracted the induced endoplasmic reticulum stress, was simultaneously enhanced. The salvational role of autophagy was supported by adding Rap/3-MA to mechanistically regulate the expression of autophagy and autophagosome formation. In summary, autophagy helps the podocytes from cell death and may contribute to sustain the longevity as a highly differentiated cell lineage. © 2014 by the Society for Experimental Biology and Medicine.

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