Fimasartan attenuates renal ischemia-reperfusion injury by modulating inflammation-related apoptosis

Fimasartan, a new angiotensin II receptor antagonist, reduces myocyte damage and stabilizes atherosclerotic plaque through its anti-inflammatory effect in animal studies. We investigated the protective effects of pretreatment with fimasartan on ischemia-reperfusion injury (IRI) in a mouse model of ischemic renal damage. C57BL/6 mice were pretreated with or without 5 (IR-F5) or 10 (IR-F10) mg/kg/day fimasartan for 3 days. Renal ischemia was induced by clamping bilateral renal vascular pedicles for 30 min. Histology, pro-inflammatory cytokines, and apoptosis assays were evaluated 24 h after IRI. Compared to the untreated group, blood urea nitrogen and serum creatinine levels were significantly lower in the IR-F10 group. IR-F10 kidneys showed less tubular necrosis and interstitial fibrosis than untreated kidneys. The expression of F4/80, a macrophage infiltration marker, and tumor necrosis factor (TNF)-α, decreased in the IR-F10 group. High-dose fimasartan treatment attenuated the upregulation of TNF-α, interleukin (IL)-1β, and IL-6 in ischemic kidneys. Fewer TUNEL positive cells were observed in IR-F10 compared to control mice. Fimasartan caused a significant decrease in caspase-3 activity and the level of Bax, and increased the Bcl-2 level. Fimasartan preserved renal function and tubular architecture from IRI in a mouse ischemic renal injury model. Fimasartan also attenuated upregulation of inflammatory cytokines and decreased apoptosis of renal tubular cells. Our results suggest that fimasartan inhibited the process of tubular injury by preventing apoptosis induced by the inflammatory pathway.

The Effect of Adenoviral-mediated Gene Transfer of Bone Morphogenic Protein-7 on Peritoneal Fibrosis in an Animal Model of Peritoneal Dialysis / 대한신장학회지

PURPOSE: TGF-beta-induced epithelial-mesenchymal transition (EMT) is associated with peritoneal fibrosis during PD. We conducted this study to evaluate the effect of BMP-7 adenoviral gene transfer on the functional and structural changes of peritoneum and whether it is associated with peritoneal EMT using an animal PD model. METHODS: Forty Sprague-Dawley rats were divided into five groups; Control (C, n=8), Dialysis (D, n= 8), Rest (R, n=8), BMP-7 (B, n=8) and LacZ (L, n=8) group. Peritoneal function was assessed on baseline, 3rd, 6th, 8th weeks after PD. Immunohistochemistry for TGF-beta, VEGF, laminin and aquaporin-1 was performed in addition to morphometric analysis of peritoneum. Immunofluorescence staining with western blotting for alpha-SMA and E-cadherin, as markers of EMT, was performed. RESULTS: The thickness of submesothelial matrix was highest in D and significantly decreased in B compared to D, R and L. D/D0 glucose at 8 weeks was significantly increased in B and L compared to that of at 6 weeks, but there were no significant differences among R, B and L at 8 weeks. TGF-beta1 and VEGF expression was observed in submesothelial matrix in D and decreased in R, B and L. Peritoneal fibrosis and functional deterioration of peritoneal membrane were associated with EMT, which was partially reversed in R, B and L. CONCLUSIONS: BMP-7 gene transfer to peritoneum was not associated with the additive therapeutic effect on peritoneal function compared to the peritoneal rest, although it improved morphologic changes of peritoneum.

Association of Transforming Growth Factor-beta1 and Vascular Endothelial Growth Factor Gene Polymorphisms with Chronic Allograft Nephropathy and Graft Survival in Korean Renal Transplant Recipients / 대한신장학회지

PURPOSE: Transforming growth factor-beta1 (TGF-beta1) has been associated with the promotion of renal allograft interstitial fibrosis and thereby chronic allograft nephropathy (CAN). Vascular endothelial growth factor (VEGF) has been shown to contribute to cytoprotection of the graft after kidney transplantation. We investigated the influence of single nucleotide polymorphisms (SNPs) of the TGF-beta1 (C-509T and T869C) and the VEGF gene (C-2578A and C405G) on graft survival and the development of CAN. METHODS: Genotyping was carried out using a real-time polymerase chain reaction which was performed on the LightCycler480 in 221 Korean renal transplant recipients and 148 healthy controls. According to the presence of CAN or chronic calcineurin inhibitor nephrotoxicity, the recipients were separated into the CAN (n=21) and the No CAN (n=200) groups. RESULTS: The genotype frequencies of the SNPs were in Hardy-Weinberg equilibrium. The distributions of genotypes and alleles did not differ between recipients and controls. No significant differences were observed in the genotype distributions and allele frequencies between the CAN and the No CAN groups. The frequencies of haplotypes were not significantly different between the two groups, either. There were no statistically significant effects of TGF-beta1 and VEGF gene polymorphisms on graft survival. CONCLUSION: This study did not show any statistically significant effects of four selected SNPs of the TGF-beta1 and the VEGF genes on the development of CAN and graft survival in Korean renal transplant recipients.

Association of Transforming Growth Factor-beta 1 Gene Polymorphisms with Atherosclerotic Vascular Disease in Peritoneal Dialysis Patients / 대한신장학회지

PURPOSE: Atherosclerotic vascular disease (AVD) is a leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD) on peritoneal dialysis (PD). Transforming growth factorbeta 1 (TGF-beta1) is a multifunctional cytokine that inhibits the atheromatous process. The author studied polymorphisms of the TGF-beta1 gene (-509C>T and 869T>C) as genetic susceptibility factors for AVD in PD patients. METHODS: Genotyping was carried out using the LightCycler 480 with melting curve analysis function. Prevalent vascular disease was defined by the presence of ischemic heart disease (IHD), peripheral vascular disease (PVD), cerebrovascular disease (CVD), or congestive heart failure (CHF). The presence of AVD was derived by the presence of any vascular disease (i.e., any degree of IHD/PVD/ CVD). RESULTS: In total, 109 PD patients were recruited (38.7% male, and 28.7% diabetic). The mean age was 49.1+/-14.1 years, and mean dialysis duration was 61.3+/-34.1 months. The most frequent genotype at -509C>T was CT (49.5%) and at 869T>C was TC (47.7%). No significant differences were observed in the genotype distributions of the investigated TGF-beta1 (CC:CT:TT, 18.5%:55.6%:25.9% vs 26.8%:47.6%:25.6%, Chi2=0.246, p=0.884; TT:TC:CC, 18.5%:55.6%:25.9% vs 28.0%:45.1%:26.8%, Chi2=1.188, p=0.552) between AVD group and no AVD group. CONCLUSION: TGF-beta1 gene polymorphisms at both -509C>T and +869T>C were not associated with an increased risk for prevalent vascular diseases. Further studies are required to evaluate the role of TGF-beta1 as a candidate gene.

Establishment of a Culture Method and Characterization for Human Fetal Astrocytes

No abstract available.

Characterization of Gene Expression Pattern in Human Astrocytes using DDRT - PCR Method

No abstract available.

Regulation of TNF - alpha Gene Expression in Human Fetal Astrocytes

Tumor necrosis factor-n (TNF - alpha) involved in the pathogenesis of multiple sclerosis and contribute to the degeneration of oligodendrocytes as well as neurons. TNF - alpha is produced by miocroglia and astrocytes, which also produce hormones and cytokines that influence its biological activity. Astrocytes, the major glial cells in the CNS, are capable of producing TNF - alpha at both the mRNA and protein levels in response to interleukine-1 (IL-1) or TNF - alpha. Two immunosuppressive cytokines, transforming growth factor - beta (TGF - beta) and IL-10, have been shown to influence glial cell function. TGF - beta can modulate the activity of glial cells by inhibiting interferon-gamma (IFN - gamma) induced expression of class II major histocompatibility complex (MHC) molecules on astrocytes and microglia. To explore the role of astrocytes in the production of TNF - alpha, astrocytes were pretreated with IL-10 or TGF - beta and then stimulated with IL-1p to determine their effects on TNF - alpha production. The secretion of TNF - alpha by human fetal astrocytes was markedly inhibited by TGF - beta at a low concentration. In contrast IL-10 had no effect on TNF - alpha mRNA level. These results show that TGF - beta may regulate the expression of TNF - alpha in activated human fetal astrocytes.