Novel Plasminogen Activator Inhibitor-1 Inhibitors Prevent Diabetic Kidney Injury in a Mouse Model.

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, but no effective therapeutic strategy is available. Because plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a key factor in extracellular matrix (ECM) accumulation in diabetic nephropathy, this study examined the renoprotective effects of TM5275 and TM5441, two novel orally active PAI-1 inhibitors that do not trigger bleeding episodes, in streptozotocin (STZ)-induced diabetic mice. TM5275 (50 mg/kg) and TM5441 (10 mg/kg) were administered orally for 16 weeks to STZ-induced diabetic and age-matched control mice.

Peritoneal Dialysate Glucose Load and Systemic Glucose Metabolism in Non-Diabetics: Results from the GLOBAL Fluid Cohort Study.

Background And Objectives: Glucose control is a significant predictor of mortality in diabetic peritoneal dialysis (PD) patients. During PD, the local toxic effects of intra-peritoneal glucose are well recognized, but despite large amounts of glucose being absorbed, the systemic effects of this in non-diabetic patients are not clear. We sought to clarify whether dialysate glucose has an effect upon systemic glucose metabolism.

High blood glucose independent of pre-existing diabetic status predicts mortality in patients initiating peritoneal dialysis therapy.

Purpose: Poor glycemic control associates with increased mortality in diabetic (DM) dialysis patients, but it is less well established whether high blood glucose (BG) independent of pre-existing diabetic status associates with mortality in dialysis patients. We assessed factors affecting BG at the start of peritoneal dialysis (PD) and its mortality-predictive impact in Korean PD patients.

Methods: In 174 PD patients (55 % males, 56 % DM), BG, nutritional status, comorbidity (CMD), and residual renal function (RRF) were assessed in conjunction with dialysis initiation.

Mortality predictive role of serum uric acid in diabetic hemodialysis patients.

Objectives: It is controversial to what extent serum uric acid (SUA) is associated with mortality in patients with chronic kidney disease undergoing hemodialysis (HD). We analyzed the predictive role of SUA in the mortality of diabetic and nondiabetic chronic kidney disease patients starting on maintenance HD therapy.

Design And Subjects: SUA was measured at the initiation of HD therapy in 319 patients (137 females and 193 diabetic patients) with mean age of 60 ± 14 years and mean estimated glomerular filtration rate of 7.

Independent effects of systemic and peritoneal inflammation on peritoneal dialysis survival.

Systemic inflammation, as evidenced by elevated inflammatory cytokines, is a feature of advanced renal failure and predicts worse survival. Dialysate IL-6 concentrations associate with variability in peritoneal small solute transport rate (PSTR), which has also been linked to patient survival. Here, we determined the link between systemic and intraperitoneal inflammation with regards to peritoneal membrane function and patient survival as part of the Global Fluid Study, a multinational, multicenter, prospective, combined incident and prevalent cohort study (n=959 patients) with up to 8 years of follow-up.

Catalase deficiency accelerates diabetic renal injury through peroxisomal dysfunction.

Mitochondrial reactive oxygen species (ROS) play an important role in diabetes complications, including diabetic nephropathy (DN). Plasma free fatty acids (FFAs) as well as glucose are increased in diabetes, and peroxisomes and mitochondria participate in FFA oxidation in an interconnected fashion. Therefore, we investigated whether deficiency of catalase, a major peroxisomal antioxidant, accelerates DN through peroxisomal dysfunction and abnormal renal FFA metabolism.

History of nephrology and renal replacement therapy in Korea.

Korea has a long tradition of Eastern (Korean) medicine. Modern nephrology in Korea began in the 20th century after the Second World War. The first nephrology report was presented in 1949 at the third annual meeting of the Korean Society of Internal Medicine.

Uremia induces functional incompetence of bone marrow-derived stromal cells.

Background: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular diseases (CVD). We hypothesized that inadequate angiogenic response in uremic patients could result from dysfunction of bone marrow-derived stromal cells [mesenchymal stem cells (MSCs)].

Methods: We investigated whether MSCs are functionally competent in uremia induced by partial kidney ablation in C57Bl/6J mice.

Renoprotective antioxidant effect of alagebrium in experimental diabetes.

Background: Despite the beneficial effects of alagebrium (ALA), a putative advanced glycation end-product (AGE) breaker, on diabetic nephropathy, its renoprotective mechanisms are incompletely understood. Since oxidative stress exacerbates diabetic renal injury through interaction with AGE, the present study examined the antioxidative property of ALA in db/db mice, mesangial cells cultured under high glucose or H(2)O(2) and a test tube.

Methods: ALA (2 mg/kg/day) was administered intraperitoneally for 12 weeks to 8-week-old db/m and db/db (D(ALA)E) mice or for 4 weeks to 16-week-old db/db mice (D(ALA)L).

Glucose-based peritoneal dialysis solution suppresses adiponectin synthesis through oxidative stress in an experimental model of peritoneal dialysis.

Objective: Accumulation of visceral fat is one of the major risk factors for the development of cardiovascular disease in peritoneal dialysis (PD) patients. Adiponectin, an adipokine commonly regarded as a negative indicator of metabolic disease, is reported to be downregulated in its gene level in end-stage renal disease patients. Since excessive fat deposit is involved in increased reactive oxygen species (ROS), PD solution (PDS) may contribute to ROS production, resulting in dysregulation of adiponectin.

Risk factors for mortality in diabetic peritoneal dialysis patients.

Background: It is well established that the survival rate of diabetic end-stage renal disease patients remains the lowest among all primary diagnoses probably because of higher prevalence of cardiovascular diseases (CVD) associated with diabetes. This study was designed to evaluate the impact of CVD and other risk factors individually or in combination on mortality in diabetic peritoneal dialysis (PD) patients.

Methods: In a retrospective study, 213 incident PD patients [118 had diabetes mellitus (DM), 94 were female, mean age 55 ± 13 years] underwent initial assessment of nutritional status, comorbid disease (CMD) survey, residual renal function (RRF), dialysis adequacy and peritoneal transport characteristics at a mean of 9 days (range, 3-24 days) after start of PD and were then followed for 30 ± 24 months (range, 3-115 months).

Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-beta1 during renal fibrosis in diabetes.

Background/aims: Plasminogen activator inhibitor (PAI)-1 is increasingly recognized as a profibrotic factor but the mechanisms are not entirely clear. The present study examined the profibrotic mechanism of PAI-1 focusing on its effect on transforming growth factor (TGF)-beta1 in experimental diabetes.

Methods: PAI-1 knockout (KO) mesangial cells cultured under high glucose (HG) in addition to streptozotocin-induced diabetic PAI-1 KO mice were used.

Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury.

Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-beta1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation.

Optimal use of peritoneal dialysis in patients with diabetes.

The survival of patients with end-stage renal disease (ESRD) resulting from diabetes continues to improve, but the survival rate among diabetic ESRD patients remains the lowest among all primary diagnoses probably because of the higher prevalence of cardiovascular comorbidity associated with diabetes. Diabetes, age, and comorbidity all significantly modify the effect of treatment modality on patient survival. As compared with hemodialysis (HD), peritoneal dialysis (PD) offers an equal or lower risk of death across all subgroups during the first 1-2 years of dialysis.

Impact of incremental risk factors on peritoneal dialysis patient survival: proposal of a simplified clinical mortality risk score.

Background/aim: Peritoneal dialysis (PD) patient survival is influenced by many factors and there is no consensus on the relative importance of these predictors, independently or combined. This study was designed to evaluate how these independent factors, alone or in various combinations, may influence PD patient survival.

Methods: A peritoneal equilibration test, subjective global assessment (SGA), and comorbid diseases (CMD) were assessed.

Role of reactive oxygen species in the pathogenesis of diabetic nephropathy.

There is an increasing evidence that reactive oxygen species (ROS) play a major role in the development of diabetic complications. Oxidative stress is increased in diabetes and the overproduction of ROS in diabetes is a direct consequence of hyperglycemia. Various types of vascular cells including renal cells are able to produce ROS under hyperglycemic condition.

Mechanisms of epithelial-mesenchymal transition of peritoneal mesothelial cells during peritoneal dialysis.

A growing body of evidence indicates that epithelial-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMC) may play an important role in the development and progression of peritoneal fibrosis during long-term peritoneal dialysis (PD) leading to failure of peritoneal membrane function. Here, we review our own observations and those of others on the mechanisms of EMT of HPMC and suggest potential therapeutic strategies to prevent EMT and peritoneal fibrosis during long-term PD. We found that high glucose and H2O2 as well as transforming growth factor-beta1 (TGF-beta1) induced EMT in HPMC and that high glucoseinduced EMT was blocked not only by inhibition of TGF-beta1 but also by antioxidants or inhibitors of mitogen-activated protein kinases (MAPK).

Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney.

Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) in the kidney. Reactive oxygen species (ROS) play a central role in the ECM synthesis and degradation in the glomeruli and tubulointerstitium leading to renal fibrosis. High glucose (HG) induces cellular ROS through protein kinase C (PKC)-dependent activation of NADPH oxidase and through mitochondrial metabolism.

Plasminogen activator inhibitor-1 and diabetic nephropathy.

Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) in the kidney. Decreased ECM degradation as well as increased ECM synthesis plays an important role in ECM remodeling that favours tissue fibrosis. Plasminogen activator (PA)/plasmin/PA inhibitor (PAI) system is involved in ECM degradation and PAI-1 plays a critical role in ECM remodeling in the kidney.

Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 up-regulation in mesangial cells and in diabetic kidney.

Background: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in remodeling of extracellular matrix (ECM) in the glomeruli. PAI-1 is up-regulated by high glucose and is overexpressed in diabetic kidney. Since reactive oxygen species (ROS) mediate ECM accumulation in diabetic glomeruli and was recently found to mediate transforming growth factor-beta1 (TGF-beta1)-induced PAI-1 up-regulation in glomerular mesangial cells, we examined the role of ROS in high glucose-induced PAI-1 expression in cultured glomerular mesangial cells and in streptozotocin-induced diabetic rat glomeruli.

Peritoneal dialysis patient survival: a comparison between a Swedish and a Korean centre.

Background: Dialysis patient mortality remains high, and this high mortality may be due to many factors. In peritoneal dialysis (PD) patients, old age, co-morbid diseases, malnutrition, low residual renal function (RRF) and a high peritoneal transport rate have been shown to influence survival, but the relative importance of these factors may differ between different patient populations. Besides, centre practice patterns may differ between centres and may influence patient survival.

Angiotensin II mediates high glucose-induced TGF-beta1 and fibronectin upregulation in HPMC through reactive oxygen species.

Objective: To demonstrate the presence of an independent renin-angiotensin system (RAS) in the peritoneum and to determine the role of locally produced angiotensin (Ang) II in high glucose-induced upregulation of transforming growth factor (TGF)-beta1 and fibronectin by human peritoneal mesothelial cells (HPMC).

Methods: In cultured HPMC, the expression of mRNAs for angiotensinogen, angiotensin-converting enzyme (ACE), Ang II type 1 receptor (AT1), and TGF-beta1 was evaluated by real-time polymerase chain reaction; ACE, AT1, and fibronectin proteins by Western blot analysis; and Ang I, Ang II, and TGF-beta1 proteins by ELISA. Dichlorofluorescein (DCF)-sensitive cellular reactive oxygen species (ROS) were measured by fluorometry.

Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells.

Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-beta1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-beta1-induced EMT. Because reactive oxygen species (ROS) are involved in TGF-beta1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-beta1-induced MAPK activation and EMT in rat proximal tubular epithelial cells.

Reactive oxygen species amplify protein kinase C signaling in high glucose-induced fibronectin expression by human peritoneal mesothelial cells.

Background: We previously demonstrated that high glucose up-regulates fibronectin mRNA and protein expression by human peritoneal mesothelial cells (HPMC) through activation of protein kinase C (PKC). PKC is known to induce cellular reactive oxygen species (ROS) and PKC-dependent activation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been shown to be responsible, in part, for increased oxidative stress in diabetes. On the other hand, high glucose-induced mitochondrial overproduction of superoxide anion was found to activate PKC.