Kei Kiribayashi

Signal transducer and activator of transcription 3 involvement in the development of renal interstitial fibrosis after unilateral ureteral obstruction

Background:  In vitro studies suggest that the signal transducer and activator of transcription (STAT) plays a critical role in renal fibrosis. However, the process of STAT activation in vivo remains unclear. This study in rats aimed to localize STAT3 activation within the kidney and examine the in vivo relationship between STAT3 activation and renal fibrosis.

Effect of Glucose polymer on the intercellular junctions of cultured human peritoneal mesothelial cells

Background: Glucose polymer is an active osmotic agent that is increasingly used as an alternative to glucose in peritoneal dialysis fluids. It was recently reported that the duration of peritoneal dialysis can be extended by using glucose polymer in patients with poor ultrafiltration. We previously demonstrated that high glucose levels damage the intercellular junctions of cultured human peritoneal mesothelial cells (HPMC), but little is known about the influence of glucose polymer. Therefore, we investigated the effects of glucose polymer on the intercellular junctions of HPMC. Methods: HPMC were isolated, cultured, and identified according to the modified method of Stylianou. M199 medium was supplemented with peritoneal dialysis solutions containing 7.5% glucose polymer or 1.5, 2.5, and 4.25% glucose. After 6 h, cell viability was assessed, intercellular junction proteins were examined by immunofluorescence techniques, and the concentration of transforming growth factor-β1 in the culture supernatant was determined. Results: Glucose significantly suppressed cell viability and significantly increased transforming growth factor-β1 production when compared with control or glucose polymer cultures. Peritoneal dialysis solutions containing 4.25% glucose caused the detachment of HPMC. Immunofluorescence of intercellular junction proteins (tight junctions: ZO-1, occludin, and claudin-1; adherens junctions: β-catenin) became weak and uneven after culture with glucose. On the other hand, glucose polymer caused little change in the immunofluorescence of these proteins when compared with control cultures. Conclusions: Glucose polymer seems to be less toxic to HPMC than glucose itself, suggesting that the glucose polymer may be better for peritoneal dialysis.

Advanced Glycation End-Products Reduce the Viability of Human Peritoneal Mesothelial Cells

Accessible online at: http://BioMedNet.com/karger Dear Sir, Advanced glycation end-products (AGEs) are produced by nonenzymatic glycation of proteins through the Maillard reaction. The accumulation of AGEs is considered to be one of the causes of aging. It has been reported recently that AGEs promote the development of vascular complications in diabetes mellitus and are involved with the development of glomerulosclerosis in patients with diabetic nephropathy [1]. It has also been reported that the level of serum AGEs is increased in patients who are treated with long-term continuous ambulatory peritoneal dialysis (CAPD) [2]. Patients who are treated with CAPD suffer from problems related to peritoneal dysfunction. Dobbie [3] reported that this peritoneal dysfunction is caused by peritonitis, or longterm use of dialysate in environments of high concentrations of glucose and low pH. Degenhardt et al. [2] reported that many of these patients have a metabolic abnormality, such as an abnormality in lipid metabolism due to the absorption of glucose from the dialysate, and that renal dysfunction causes an increase in the level of serum AGEs. Peritoneal dysfunction may be caused by the serum AGEs becoming trapped in the peritoneal tissues during the process of dialysis, or by proteins in the peritoneal tissues being glycated by the high concentrations of glucose. All of these studies suggest that patients who are treated with CAPD are placed under conditions which cause the accumulation of AGEs in their peritoneal tissues. In fact, Nakayama et al. [4] have shown through immunohistological studies that AGEs accumulate Fig. 1. [3H]-thymidine incorporation of human peritoneal mesothelial cells were incubated with AGEs for 24 h. AGEs were recognized by anticarboxymethyl monoclonal antibody in this study. All experiments were done in triplicate. Data are expressed as mean B SD. Statistical analysis was done using ANOVA (* p ! 0.05, ** p ! 0.01). ✽✽

15‐Deoxy‐Δ12,14‐prostaglandin J2 Inhibits Angiotensin II‐induced Fibronectin Expression via Hepatocyte Growth Factor Induction in Human Peritoneal Mesothelial Cells

15‐Deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) is an endogenous peroxisome proliferator‐activated receptor γ (PPARγ) agonist that suppresses progressive matrix deposition; however, little is known about the effects of 15d‐PGJ2 on human peritoneal mesothelial cells (HPMCs). We investigated the following: (i) the expression of PPARγ; (ii) the effect of 15d‐PGJ2 on angiotensin II (Ang II)‐induced fibronectin (FN) expression and secretion; (iii) the effect of 15d‐PGJ2 (with or without Ang II and with or without the specific PPARγ antagonist GW9662) and pioglitazone, a synthetic PPARγ agonist, on hepatocyte growth factor (HGF) expression and secretion; (iv) the effect of HGF on Ang II‐induced FN expression and secretion; (v) the expression of c‐Met (a specific HGF receptor) and its phospho‐signal; and (vi) the involvement of HGF in the effect produced by 15d‐PGJ2 using selective c‐Met inhibitor PHA‐665752. The presence of PPARγ was detected by western blot analysis. 15d‐PGJ2 inhibited Ang II‐induced FN expression and increased HGF expression, even in the presence of Ang II. This effect of HGF expression was completely prevented by co‐treatment with GW9662. Additionally, upregulation of HGF secretion induced by 15d‐PGJ2 and HGF production induced by pioglitazone was revealed. We demonstrated the presence of c‐Met, and presented evidence that HGF inhibits Ang II‐induced FN expression and activates phosphorylation of c‐Met, which is blocked by PHA‐665752; 15d‐PGJ2 also activated c‐Met phosphorylation. Furthermore, PHA‐665752 attenuates the inhibitory effects of 15d‐PGJ2 on FN secretion. These findings suggest that 15d‐PGJ2 has a novel and potent antifibrotic effect in HPMC and this action is likely mediated by HGF.

Vitamin K_2 Alters Bone Metabolism Markers in Hemodialysis Patients with a Low Serum Parathyroid Hormone Level

Background: A low level of intact parathyroid hormone (PTH) is an indicator of adynamic bone disease in hemodialysis patients, and is associated with a significant increase of all-cause mortality. Thus, effective treatment for adynamic bone disease is required. We previously investigated the effect of vitamin K2 on adynamic bone disease. In this study, we assessed the efficacy of oral vitamin K2 in a controlled trial. Methods: Forty hemodialysis patients with low intact PTH levels (<100 pg/ml) were randomly divided into two groups, which were a vitamin K2 group receiving oral menatetrenone (45 mg/day) for 1 year and a control group without vitamin K2. Venous blood samples were collected at baseline and during the study for measurement of bone metabolism parameters. Results: Thirty-three patients completed follow-up. There was a significant increase of the serum intact osteocalcin level after 1 month of vitamin K2 administration. Serum levels of intact PTH, bone alkaline phosphatase, and cross-linked N-terminal telopeptide of type I collagen increased significantly after 12 months in the vitamin K2 group. The serum osteoprotegerin level was decreased after 12 months in the vitamin K2 group, but the change was not significant. Conclusion: Vitamin K2 therapy improves bone remodeling in hemodialysis patients with a low intact PTH level.