Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort.

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands.

High glucose promotes TGF-ß1 production by inducing FOS expression in human peritoneal mesothelial cells.

BACKGROUND: High glucose (HG) induces production of transforming growth factor-beta1 (TGF-ß1), but the mechanism remains elusive. The aim of this study was to determine the gene(s) involved in HG-induced TGF-ß1 production in human peritoneal mesothelial cells (HPMCs). METHODS: Microarray analysis was performed following a 3-h preincubation of HPMCs in 4 or 0.1% glucose medium. Transcriptional genes were selected using Gene Ontology analysis for biological processes, including regulation of transcription and DNA-dependent. The effects of small interfering RNA (siRNA) treatments on the up-regulation of TGF-ß1 mRNA were assessed by quantitative real-time polymerase chain reaction (qPCR). Finally, enzyme-linked immunosorbent assay (ELISA) was performed to determine which gene(s) contribute to the production of TGF-ß1 protein in the medium. RESULTS: Microarray analysis revealed that the expression of 51 genes increased by more than 3-fold. Gene ontology analysis identified 13 genes for further study. qPCR confirmed mRNA amplification for 9 of the 13 genes. Furthermore, HG-induced up-regulation of TGF-ß1 mRNA was attenuated by the siRNA of 4 genes: MDS1 and EVI1 complex locus (MECOM), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), FBJ murine osteosarcoma viral oncogene homolog (FOS) and activating transcription factor 3 (ATF3). ELISA showed that siRNA treatment of FOS, but not MECOM, FOSB or ATF3, suppressed the increase of TGF-ß1 protein in the medium. CONCLUSIONS: FOS is a downstream effector of HG stimulation in HPMCs that contributes to TGF-ß1 production, suggesting that blocking FOS expression may be a therapeutic target for peritoneal fibrosis.

Efficacy of add-on therapy of aliskiren to an angiotensin II receptor blocker on renal outcomes in advanced-stage chronic kidney disease: a prospective, randomized, open-label study.

BACKGROUND: Combination therapy of aliskiren and an angiotensin II receptor blocker (ARB) has been reported to be effective for reducing the level of proteinuria. However, it remains unclear whether this combination therapy contributes to suppression of kidney disease progression. The aim of this study was to investigate the effect of aliskiren on hard renal endpoints, when added to an ARB, in patients with advanced chronic kidney disease (CKD). METHODS: The study design was a prospective, randomized open-label design. 83 CKD patients (52 men and 31 women) were enrolled and assigned randomly to an aliskiren add-on group (n = 42) or control group (n = 41). Entry criteria included elevated serum creatinine ≥ 1.5 mg/dl, urine protein excretion (≥ 1+ on urine dipstick test), and hypertension. All participants were treated with an ARB. The follow-up period was 12 months. 12 participants were withdrawn during the study period and the study was terminated in January 2012 as a consequence of the results of the interim analysis of the ALTITUDE study. RESULTS: Nine patients in the aliskiren group and seven patients in the control group started dialysis. Doubling of the serum creatinine level occurred in one patient in the control group. A Cox proportional hazards test showed that dual blockade of the renin-angiotensin-aldosterone system with aliskiren and ARB was not associated with improvement in hard renal endpoints. CONCLUSION: We conclude that aliskiren add-on therapy to an ARB may not give any benefit and, therefore, should not be recommended in CKD patients.

Fast and Efficient Separation and Determination of UV-absorbing Amino Acids, Nucleobases, and Creatinine Using a Carboxy-functionalized Cation-exchange Column.

This paper presents a new HPLC technique for the determination of biogenic cations such as amino acids and nucleobases, using a weak-acid cation-exchange column. Fourteen analytes, five amino acids and seven bases in addition to creatinine and creatine, were separated in 12 min by means of a two-liquid gradient elution with UV detection. The newly released column packed with a carboxy-functionalized polymethacrylate resin could give excellent selectivity to the organic cations of interest, although such a column is in general suitable for the separation of inorganic common cations. The chromatographic intra-day repeatability was very good with RSDs less than 0.4%, and the quantitation precision based on peak area intensities was also good with RSDs less than 5% for all analytes. The linear calibration lines for quantitation ranged between 5 and 500 µM on 20-µL injections with R(2) more than 0.9990. Since the method could provide concentration data of urinary creatinine and some metabolites simultaneously, for example, the urinary phenylalanine/creatinine ratios for phenylketonuria of inborn errors of metabolism were simply determined through one chromatographic run. The ratios for patients were significantly higher than those for controls. We found that the new weak-acid cation-exchange column was suitable for the separation of organic cations as well as inorganic cations.

The serum lipids levels may be underestimated in patients on hemodialysis.

OBJECTIVE: Although lipid disorders are a well-known risk factor for cardiovascular disease (CVD) in the general population, the optimal management with lipid-lowering therapy to reduce CVD risks and mortality in hemodialysis (HD) patients remains controversial. In the clinical setting, dyslipidemia can be diagnosed based on the detection of elevated lipid concentrations at the beginning of HD. This study investigated changes in the levels of serum lipids during a single HD session. METHODS: The serum total cholesterol, triglyceride and high-density lipoprotein (HDL) cholesterol levels were measured in 31 HD patients at zero, two and four hours after the beginning of a single HD session. The data were analyzed using the Wilcoxon signed-rank test, a linear mixed model and Spearman's rank correlation analysis. RESULTS: The serum total cholesterol, HDL cholesterol and non-HDL cholesterol levels increased significantly during the HD session. Even after the lipid parameters were corrected for changes in the total protein level, the total cholesterol and HDL cholesterol levels increased, whereas the non-HDL cholesterol levels did not change significantly. The percentage change in the serum levels of these lipid fractions correlated strongly with the percentage change in the ultrafiltration volume per body weight. In contrast, the serum triglyceride levels were decreased significantly at two hours compared with the levels noted at the beginning of HD and gradually increased at four hours. CONCLUSION: The serum lipid levels are influenced significantly by HD treatment and ultrafiltration. Evaluating the degree of dyslipidemia at the beginning of a HD session may therefore underestimate the levels of serum lipids in HD patients with a large amount of weight gain, thus resulting in the use of insufficient lipid-lowering therapy.

Expression of age-related factors during the development of renal damage in patients with IgA nephropathy.

BACKGROUND: Chronic kidney disease patients share clinical and pathological features with the general aging population. Increased oxidative DNA damage, accumulation of cell cycle-arrested cells and decreased Klotho expression are assumed to be age-related factors that are reportedly linked to kidney disease. This study sought to determine the association between these age-related factors and renal damage in patients with IgA nephropathy (IgAN). METHODS: We performed a cross-sectional analysis of 71 patients who were diagnosed with IgAN by renal biopsy. Expression of 8-hydroxydeoxyguanosine (8-OHdG, a marker of oxidative DNA damage), p16 (a marker of cell cycle-arrest) and Klotho (an anti-aging protein) were evaluated by immunohistochemical staining of renal biopsy samples. We correlated the changes in expression of these markers with Lee's pathologic grades and the Oxford classification. We also investigated the independent association between these markers and interstitial fibrosis using multiple linear regression analysis. RESULTS: 8-OHdG and p16 increased but Klotho decreased with progression of pathologic grade. Expression of 8-OHdG and p16 increased with the deterioration of mesangial hypercellularity and segmental glomerulosclerosis. In addition, p16 increased but Klotho decreased with progression of tubular atrophy/interstitial fibrosis. In univariate regression analysis, age, body mass index, systolic blood pressure, urinary protein excretion and expression of 8-OHdG, p16 and Klotho showed significant correlations with interstitial fibrosis. Multivariable regression analyses revealed that aging, increased renal expression of p16 and decreased expression of Klotho were independently correlated with interstitial fibrosis. CONCLUSIONS: The age-related factors might play important roles in the development of IgAN.

Mizoribine ameliorates renal injury and hypertension along with the attenuation of renal caspase-1 expression in aldosterone-salt-treated rats.

Aldosterone-salt treatment induces not only hypertension but also extensive inflammation that contributes to fibrosis in the rat kidney. However, the mechanism underlying aldosterone-salt-induced renal inflammation remains unclear. Pyroptosis has recently been identified as a new type of cell death that is accompanied by the activation of inflammatory cytokines. We hypothesized that aldosterone-salt treatment could induce inflammation through pyroptosis and that mizoribine, an effective immunosuppressant, would ameliorate the renal inflammation that would otherwise cause renal fibrosis. Ten days after recovery from left uninephrectomy, rats were given drinking water with 1% sodium chloride. The animals were divided into three groups (n = 7 per group): (1) vehicle infusion group, (2) aldosterone infusion group, or (3) aldosterone infusion plus oral mizoribine group. Aldosterone-salt treatment increased the expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 and caspase-1, and also increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. However, the oral administration of mizoribine attenuated these alterations. Furthermore, mizoribine inhibited hypertension and renal fibrosis, and also attenuated the aldosterone-induced expression of serum/glucocorticoid-regulated kinase and α epithelial sodium channel. These results suggest that caspase-1 activation plays an important role in the development of inflammation induced by aldosterone-salt treatment and that it functions as an anti-inflammatory strategy that protects against renal injury and hypertension.

Mesenchymal stem cells ameliorate experimental peritoneal fibrosis by suppressing inflammation and inhibiting TGF-ß1 signaling.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have regenerative capability and exert paracrine actions on damaged tissues. Since peritoneal fibrosis is a serious complication of peritoneal dialysis, we tested whether MSCs suppress this using a chlorhexidine gluconate model in rats. Although MSCs isolated from green fluorescent protein-positive rats were detected for only 3 days following their injection, immunohistochemical staining showed that MSCs suppressed the expression of mesenchymal cells, their effects on the deposition of extracellular matrix proteins, and the infiltration of macrophages for 14 days. Moreover, MSCs reduced the functional impairment of the peritoneal membrane. Cocultures of MSCs and human peritoneal mesothelial cells using a Transwell system indicated that the beneficial effects of MSCs on the glucose-induced upregulation of transforming growth factor-ß1(TGF-ß1) and fibronectin mRNA expression in the human cells were likely due to paracrine actions. Preincubation in MSC-conditioned medium suppressed TGF-ß1-induced epithelial-to-mesenchymal transition, α-smooth muscle actin, and the decrease in zonula occludens-1 in cultured human peritoneal mesothelial cells. Although bone morphogenic protein 7 was not detected, MSCs secreted hepatocyte growth factor and a neutralizing antibody to this inhibited TGF-ß1 signaling. Thus, our findings imply that MSCs ameliorate experimental peritoneal fibrosis by suppressing inflammation and TGF-ß1 signaling in a paracrine manner.

Polyfunctional low-capacity cation-exchange packing material for the separation of underivatized amino acids.

A polyfunctional low-capacity cation-exchange column-packing material was developed for the simultaneous separation and determination of underivatized 20 amino acids including 16 proteinogenic ones using a binary gradient HPLC. The new packing material was prepared by sulfoacylating a highly crosslinked macroreticular poly(styrene-divinylbenzene) copolymer of 3 µm in diameter commercially available for size-exclusion chromatography. The polyfunctionality could derive from unintentional carboxy groups innately present in the base polymers probably came from polymerization initiators in addition to the intentionally introduced sulfopropionyl groups, which was certified and evaluated by measuring dynamic capacity curves of the cation exchanger. Sixteen underivatized proteinogenic amino acids were separated in 23 min using a binary high-pressure gradient elution system with two liquids of 1 mmol L(-1) H(3)PO(4) and 20 mmol L(-1) NaH(2)PO(4)/30% (v/v) CH(3)CN, which led to the cycle time of 25 min. In the case of separation of 20 amino acids, the cycle time was 27 min. The developed low-capacity cation-exchange chromatography with post-column fluorescence detection was sufficiently quantitative, providing linear calibration lines ranged through almost three digit for all analytes. The detection limits were calculated as nmol L(-1) order of magnitude with 20-µL injection. The method was applicable to the direct analysis of urinary amino acids of diagnostic markers for inborn errors of metabolism.

Morning blood pressure is useful for detection of left ventricular hypertrophy in hemodialysis patients.

BACKGROUND: When diagnosing hypertension (HT) it is essential to determine not only the level of raised blood pressure (BP), but also how the condition relates to organ damage. The best time to measure BP for diagnosing HT in patients on hemodialysis (HD) remains unclear. METHODS: A total of 100 HD patients (mean age 63.8 years, 60 males) were studied. Left ventricular hypertrophy (LVH) was detected by echocardiography and BP monitored for 1 week at 20 different times in the morning and night, before and after dialysis. We also checked for masked HT, i.e., patients with weekly morning HT, but not pre-dialysis HT. RESULTS: Average BP for the week was 141.9 ±19.0/79.6 ± 10.6 mmHg, with 68 patients classified as hypertensive. Average morning BP was 144.6 ± 19.8/81.7 ± 11.3 mmHg, and 71 patients had weekly morning HT. In addition, 62 patients had LVH and 51 patients had relative morning HT. Multiple logistic analyses showed that LVH was associated with weekly morning HT, morning HT on HD and non-HD days, average HT, and relative morning HT. However, evening, pre-dialysis, and post-dialysis HT showed no association with LVH. Masked HT was found in 20 % of patients. If HT had been diagnosed using only pre-dialysis BP, 20 of the 71 patients with weekly morning HT would not have been detected. CONCLUSION: Morning BP is useful for detecting LVH in HD patients. Monitoring of morning BP may be superior to measurements taken at other times for diagnosing HT.

Spectrometric determination of anionic surfactants in environmental waters based on anisole extraction of their bis[2-(5-chloro-2-pyridylazo)-5-diethylaminophenolato]cobalt(III) ion pairs.

A spectrometric method for the determination of anionic surfactants in environmental water samples using the [Co(III)-(5-Cl-PADAP)(2)](+) chromophore was technically improved for practical use. An anisole-extraction procedure was alternatively introduced and optimized in place of the earlier benzene-extraction procedure. The molar absorptivity for SDS found by the Co(III)-5-Cl-PADAP/anisole method was 72000 L mol(-1) cm(-1) at 560 nm, which was ca. 1.3-times higher than those by the Co(III)-5-Cl-PADAP/benzene method. The analytical sensitivity was almost independent of the kind of anionic surfactants. The calibration lines for SDS, LAS, and SSS were all linear between 1.0 × 10(-7) and 1.0 × 10(-5) mol L(-1) with acceptable r(2) values of 0.9998, 0.9995, and 0.9999, respectively. The method was applied to the analyses of river, well, and seawater samples, providing the compatible results by means of the standard-addition method. In the case of seawater, a phase-washing treatment of the extracted species using dilute HCl was effective to decrease the high blank absorbance. The Co(III)-5-Cl-PADAP/anisole method, showing no glass-adsorption problem, is more advantageous than the methylene-blue and ethyl-violet methods.

[N-terminal pro brain natriuretic peptide predicts hospitalization of hemodialysis patients for cardiovascular disease].

We investigated whether or not N-terminal pro brain natriuretic peptide (NT-proBNP) could predict hospitalization for cardiovascular disease (CVD) among Japanese hemodialysis patients. A total of 104 patients on maintenance dialysis 3 times per week were enrolled. We followed the patients for 23.9 +/- 4.2 months and 19 hospitalizations for CVD occurring during this period. The area under the curve (AUC) for the risk of CVD hospitalization was calculated after drawing a receiver operating characteristic curve. Predialysis NT-proBNP showed a larger AUC value than both postdialysis NT-proBNP and brain natriuretic peptide. The optimal cut-off value of predialysis NT-proBNP for predicting CVD hospitalization was 5,894 pg/mL, (sensitivity of 60 % and specificity of 76 %). Diabetes mellitus, a history of CVD, and the predialysis NT-proBNP level were significant determinants of CVD hospitalization according to Cox proportional hazards analysis. In conclusion, predialysis NT-proBNP is useful for predicting CVD hospitalization in hemodialysis patients.

15-Deoxy-Delta12,14-prostaglandin J2 inhibits angiotensin II-induced fibronectin expression via hepatocyte growth factor induction in human peritoneal mesothelial cells.

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that suppresses progressive matrix deposition; however, little is known about the effects of 15d-PGJ(2) on human peritoneal mesothelial cells (HPMCs). We investigated the following: (i) the expression of PPARgamma; (ii) the effect of 15d-PGJ(2) on angiotensin II (Ang II)-induced fibronectin (FN) expression and secretion; (iii) the effect of 15d-PGJ(2) (with or without Ang II and with or without the specific PPARgamma antagonist GW9662) and pioglitazone, a synthetic PPARgamma 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-PGJ(2) using selective c-Met inhibitor PHA-665752. The presence of PPARgamma was detected by western blot analysis. 15d-PGJ(2) 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-PGJ(2) 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-PGJ(2) also activated c-Met phosphorylation. Furthermore, PHA-665752 attenuates the inhibitory effects of 15d-PGJ(2) on FN secretion. These findings suggest that 15d-PGJ(2) has a novel and potent antifibrotic effect in HPMC and this action is likely mediated by HGF.

Determination of effective capacities of ion-exchangeable materials by measuring the equilibrium conductivity.

The effective ion-exchange capacities of ion-exchange materials were determined by measuring the change in the equilibrium conductivity of a column packed with analyte. The developed instrumental method can provide effective ion-exchange capacities for both cation and anion exchangers with simple operations. The cation-exchange capacity of a weak-acid cation-exchange resin (TSKgel SuperIC-Cation column) depended on the conditioning pH and the molar concentration of the conditioning agent. Plots of effective cation-exchange capacities over the conditioning pH exhibited three inflection points, suggesting the presence of two carboxy groups and one phenolic OH group in the resin, probably due to the inherent base polymer. This method was applied to several commercial analytical columns for ion chromatography, and could provide scientifically useful results for characterizing the resin properties.

[The role of PPARgamma agonists in kidney diseases].

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that has a central role in the regulation of insulin sensitivity and adipocyte differentiation. Expression of PPARgamma has been reported in the kidney, including medullary collecting ducts, glomeruli and tubular cells. Thiazolidinediones (TZDs) are synthetic PPARgamma agonists and are used widely in patients with type 2 diabetes. It has been gradually discovered that TZDs have various other actions, such as vascular protective, anti-inflammatory, anti-fibrotic and anti-proliferative actions, over and above their effects on glucose and lipid metabolism. In this review, we will focus on current knowledge and insights on the role of PPARgamma agonists in kidney diseases, especially in diabetic nephropathy, non-diabetic kidney diseases and dialysis therapy.

Effect of the amount of liquid phase in packed column GC on air oxidation product of methyl oleate.

The analysis or preparative isolation of a specimen by a packed column gas chromatograph is affected by the kind and amount (concentration) of the liquid phase coated on the stationary phase. In particular, compounds having the same or similar molecular weight and similar functional groups are largely affected. Methyl oleate, which is a typical component of fats and oils, produces hydroperoxide by air oxidation as a first step. After that, various oxygenated compounds with a carbon number of 19 are produced. In this study, the effect of the concentration of ethylene glycol succinate polyester (EGS) as the liquid phase was examined for these compounds. The retention time of the hydroxides increased with an increase in the EGS concentration. The effect of the EGS concentration on the retention time decreased when these compounds were trimethyl silylated (TMS). The retention time of epoxides and oxo compounds increased with an increase in the EGS concentration independently of trimethyl silylation. Correction values were required for all quantitation.

Simultaneous determination of silicate and phosphate in environmental waters using pre-column derivatization ion-pair liquid chromatography.

A highly sensitive HPLC method for the simultaneous determination of soluble silicate and phosphate in environmental waters was developed, using ion-pair liquid chromatography preceded by the formation of their yellow alpha-heteropolymolybdates. The moderate-pH mobile phase enabled to use a highly efficient reversed-phase silica column. The pre-column coloring reactions at moderate-pH were reproducible for both silicate and phosphate in all quantification ranges with R.S.D.s less than 2% and 5%, respectively. The linear calibration lines between concentrations (mg-SiO(2)/L and mg-PO(4)/L) and peak area intensities were obtained for silicate and phosphate both with acceptable determination coefficients (r(2)) of 0.9999. The limits of determination for both analytes were 0.007 mg-SiO(2)/L and 0.003 mg-PO(4)/L, which were calculated theoretically using 10sigma/slope. The four-digit dynamic ranges were obtained for 0.007-10mg-SiO(2)/L and 0.003-20mg-PO(4)/L. The developed method was applied for the analysis of tap water, river water, coastal seawater, well water, hot-spring water, commercial mineral water, and laboratory water. The results were very reasonable and acceptable from the environmental viewpoints, which were well correlated with those confirmed by the molybdenum-blue spectrophotometry.

PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta.

Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligands, have a central role in insulin sensitization and adipogenesis. It has been reported that TZDs exert protective effects in both diabetic and nondiabetic models of renal disease, although the exact mechanism is not well understood. In particular, only a few studies have reported the renoprotective effects of TZDs in nondiabetic models of tubulointerstitial fibrosis and inflammation. Therefore, we investigated the anti-fibrotic and anti-inflammatory effects of the TZD troglitazone in the mouse model of unilateral ureteral obstruction (UUO). C57BL/6J mice underwent UUO and were studied after 3 and 7 days. Animals were divided into three groups and received control vehicle, troglitazone (150 mg/kg per day) or troglitazone (300 mg/kg per day) by gavage. Kidneys were harvested for morphological, mRNA and protein analysis. Reverse-transcriptase-PCR was used to assess the expression of transforming growth factor-beta1 (TGF-beta1) and the TGF-beta1 type I receptor (TGF beta R-I). Protein expression was assessed by western blotting (TGF beta R-I) and immunostaining (TGF beta R-I, alpha-smooth muscle actin (alpha-SMA), type I collagen (collagen I), F4/80, and proliferating cell nuclear antigen (PCNA)). The expression of alpha-SMA, collagen I, and F4/80 was decreased in mice treated with troglitazone compared with the control group. The numbers of PCNA-positive interstitial cells were decreased in mice treated with troglitazone. TGF-beta1 mRNA and TGF beta R-I mRNA and protein expression were decreased in the group treated with troglitazone compared with the control group. The beneficial effects of troglitazone treatment were also dose dependent. PPAR-gamma agonist significantly reduced TGF-beta and attenuated renal interstitial fibrosis and inflammation in the model of UUO.

An oral adsorbent, AST-120, combined with a low-protein diet and RAS blocker, for chronic kidney disease.

BACKGROUND: A low-protein diet and treatment with renin-angiotensin system (RAS) blockers can delay the progression of chronic kidney disease (CKD). The oral adsorbent AST-120 (Kremezin) has a renoprotective effect by reducing serum levels of uremic toxins. We investigated the influence of AST-120 on the preservation of renal function in patients with CKD. METHODS: Twenty-eight patients were randomized to 2 groups: 15 patients receiving 6.0 g of AST-120 daily for 12 months plus a low-protein diet and RAS blocker therapy (group A) and 13 patients who were not given AST-120 (group B). All of them had shown progressive deterioration of renal function with basal treatment. Mean baseline serum creatinine level (+/- standard deviation) was 2.4 +/- 0.8 mg/dL in group A and 2.7 +/- 0.8 mg/dL in group B. There were no significant differences in background parameters before AST-120 therapy. RESULTS: The change in the estimated glomerular filtration rate (eGFR) was significantly smaller in group A than in group B. The change was also significantly smaller in patients with a baseline serum creatinine <2.4 mg/dL and in patients with rapid progression. After 12 months, the slope of the eGFR curve was significantly less steep compared with baseline in group A (-1.77 vs. -0.52 ml/min per month), but there was no significant change in group B. The slope was also significantly less steep in patients with rapid progression. CONCLUSIONS: Adding AST-120 to a low-protein diet and RAS blocker therapy may delay the deterioration of chronic renal failure, especially in patients with early or rapid progression.

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. METHODS: Unilateral ureteral obstruction (UUO) was induced in the rats and the kidneys examined 3 or 7 days after obstruction. Activation of STAT3 in western blot and immunohistochemical analyses was identified by the phosphorylated form of STAT3 (pSTAT3). RESULTS: Myofibroblasts were identified by alpha-smooth muscle actin expression and were upregulated in obstructed kidneys. pSTAT3 was localized mainly in tubular epithelial cells of collecting ducts in normal and obstructed kidneys and interstitial cells in obstructed kidneys. After UUO, western blotting showed a fourfold increase in pSTAT3, with a peak at day 7. Immunostaining showed a sixfold increase in pSTAT3 at day 7 in tubular epithelial cells and a 2500-fold increase at day 7 in interstitial cells. CONCLUSION: STAT3 was activated in rat tubular epithelial cells and myofibroblasts after UUO, suggesting that STAT3 may contribute to the progression of interstitial fibrosis.