Abstract. Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM) in the kidney. TGF-␤1 has been identified as the key mediator of ECM accumulation in diabetic kidney. High glucose induces TGF-␤1 in glomerular mesangial and tubular epithelial cells and in diabetic kidney. Antioxidants inhibit high glucoseinduced TGF-␤1 and ECM expression in glomerular mesangial and tubular epithelial cells and ameliorate features of diabetic nephropathy, suggesting that oxidative stress plays an important role in diabetic renal injury. High glucose induces intracellular reactive oxygen species (ROS) in mesangial and tubular epithelial cells. High glucose-induced ROS in mesangial cells can be effectively blocked by inhibition of protein kinase C (PKC), NADPH oxidase, and mitochondrial electron transfer chain complex I, suggesting that PKC, NADPH oxidase, and mitochondrial metabolism all play a role in high glucoseinduced ROS generation. Advanced glycation end products, TGF-␤1, and angiotensin II can also induce ROS generation and may amplify high glucose-activated signaling in diabetic kidney. Both high glucose and ROS activate signal transduction cascade (PKC, mitogen-activated protein kinases, and janus kinase/signal transducers and activators of transcription) and transcription factors (nuclear factor-B, activated protein-1, and specificity protein 1) and upregulate TGF-␤1 and ECM genes and proteins. These observations suggest that ROS act as intracellular messengers and integral glucose signaling molecules in diabetic kidney. Future studies elucidating various other target molecules activated by ROS in renal cells cultured under high glucose or in diabetic kidney will allow a better understanding of the final cellular responses to high glucose. Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM) in the kidney, leading to glomerular mesangial expansion and tubulointerstitial fibrosis. Clinical studies (1,2) have demonstrated that high blood glucose is the main determinant of initiation and progression of diabetic vascular complications including nephropathy. High glucose induces reactive oxygen species (ROS) (3,4) and upregulates TGF-␤1 (5,6) and ECM (5-7) expression in the glomerular mesangial cells. Exogenous hydrogen peroxide (H 2 O 2 ) or H 2 O 2 continuously generated by glucose oxidase (GO) also upregulates TGF-␤1 and fibronectin expression in mesangial cells (4,8) and fibronectin in tubular epithelial cells (9). Finally, antioxidants effectively inhibit high glucose-and H 2 O 2 -induced TGF-␤1 and fibronectin upregulation (4,8,9 -11), thus providing evidence that ROS play an important role in high glucose-induced renal injury. ROS-regulated signaling pathways leading to final renal cellular responses in diabetic kidney are not entirely clear, however.In this article, we review the mechanisms of high glucoseinduced ROS generation and ROS-induced activation of signal transduction cascade and transcription factors and overexpression of genes and pr...

Reactive oxygen species as glucose signaling molecules in mes-stress is defined as a tissue injury induced by increase in angial cells cultured under high glucose.reactive oxygen species (ROS) such as hydrogen perox-Background. Oxidative stress is one of the important mediaide (H 2 O 2 ), superoxide anion (O 2 •Ϫ ), and hydroxyl radical tors of vascular complications in diabetes including nephrop-( • OH) and is one of the proposed mechanisms involved athy. High glucose (HG) generates reactive oxygen species in diabetic complications [3][4][5]. A pathogenic role of (ROS) as a result of glucose auto-oxidation, metabolism, and formation of advanced glycosylation end products. The concept

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. Data collected included patient demographic characteristics, comorbidity, modality, dialysis prescription, and peritoneal membrane function. Dialysate and plasma cytokines were measured by electrochemiluminescence. A total of 426 survival endpoints occurred in 559 incident and 358 prevalent patients from 10 centers in Korea, Canada, and the United Kingdom. On patient entry to the study, systemic and intraperitoneal cytokine networks were dissociated, with evidence of local cytokine production within the peritoneum. After adjustment for multiple covariates, systemic inflammation was associated with age and comorbidity and independently predicted patient survival in both incident and prevalent cohorts. In contrast, intraperitoneal inflammation was the most important determinant of PSTR but did not affect survival. In prevalent patients, the relationship between local inflammation and membrane function persisted but did not account for an increased mortality associated with faster PSTR. These data suggest that systemic and local intraperitoneal inflammation reflect distinct processes and consequences in patients treated with peritoneal dialysis, so their prevention may require different therapeutic approaches; the significance of intraperitoneal inflammation requires further elucidation.

The present data demonstrate that high glucose up-regulates TGF-beta 1 and FN synthesis by HPMC, and that this high glucose-induced up-regulation is largely mediated by PKC. These results suggest that activation of PKC by high glucose in conventional PD solutions may constitute an important signal for activation of HPMC, leading to progressive accumulation of extracellular matrix and eventual peritoneal fibrosis.

Abstract. Excessive deposition of extracellular matrix (ECM) in the kidney is the hallmark of diabetic nephropathy. Although the amount of ECM deposited in the kidney depends on the balance between the synthesis and degradation of ECM, the role of ECM degradation in matrix remodeling has been less well appreciated. High glucose, advanced glycation end products, angiotensin II, and TGF-␤1 all increase intracellular reactive oxygen species (ROS) in renal cells and contribute to the development and progression of diabetic renal injury. The role of ROS in increased ECM synthesis has been well documented. ROS may also play a critical role in decreased ECM degradation by mediating high glucose-and TGF-␤1-induced inhibition of the proteolytic system, plasmin, and matrix metalloproteinases in the glomeruli. A recent observation suggests that ROS play an important role in tubulointerstitial fibrosis by mediating TGF-␤1-induced epithelial-mesenchymal transition (EMT). Accelerated ECM degradation is required to disrupt tubular basement membrane and complete EMT. ROS thus seem to be involved in both decreased and increased ECM degradation. It is not clear how cells determine when and where to increase or decrease ECM degradation in response to ROS. Precise definition of ROS-activated signaling pathways leading to ECM remodeling in the kidney will provide new strategies to prevent or treat diabetic renal injury.