NF-kappa B signaling is required for the maintenance of normal B lymphocytes, whereas dysregulated NF-kappa B activation contributes to B cell lymphomas. The events that regulate NF-kappa B signaling in B lymphocytes are poorly defined. Here, we demonstrate that PKC-beta is specifically required for B cell receptor (BCR)-mediated NF-kappa B activation. B cells from protein kinase C-beta (PKC-beta)-deficient mice failed to recruit the I kappa B kinase (IKK) complex into lipid rafts, activate IKK, degrade I kappa B or up-regulate NF-kappa B-dependent survival signals. Inhibition of PKC-beta promoted cell death in B lymphomas characterized by exaggerated NF-kappa B activity. Together, these data define an essential role for PKC-beta in BCR survival signaling and highlight PKC-beta as a key therapeutic target for B-lineage malignancies.

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Mutations in Bruton's tyrosine kinase (Btk) result in X-linked agammaglobulinemia (XLA) in humans and X-linked immunode®ciency (xid) in mice. While targeted disruption of the protein kinase C-b (PKCb) gene in mice results in an immunode®ciency similar to xid, the overall tyrosine phosphorylation of Btk is signi®cantly enhanced in PKCb-de®cient B cells. We provide direct evidence that PKCb acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCb results in a dramatic increase in B-cell receptor (BCR)-mediated Ca 2+ signaling. We identi®ed a highly conserved PKCb serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FceRI-mediated signaling in B and mast cells, respectively. These ®ndings provide a novel mechanism whereby reversible translocation of Btk/Tec kinases regulates the threshold for immunoreceptor signaling and thereby modulates lymphocyte activation. Keywords: BCR signaling/Bruton's tyrosine kinase/ calcium signaling/membrane localization/protein kinase C IntroductionAggregation of antigen receptors on B cells leads to the concerted activation of non-receptor tyrosine kinases, including Src, Syk and Tec family kinases, and lipid kinases including phosphoinositide 3-kinase (PI3K) (Kurosaki, 1999;Rawlings, 1999;Yang et al., 2000). These events initiate the formation of a multimeric signaling complex termed the signalosome. The signalosome promotes enhanced catalytic activity of phospholipase C-g2 (PLCg2) and the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These second messengers lead to intracellular calcium mobilization and protein kinase C (PKC) activation, respectively (Fruman et al., 2000). Synergistic signaling by PKC isoforms and calcium is important in the activation of transcription factors leading to diverse biological responses in activated B cells Healy et al., 1997). Notably, the signalosome complex integrates both positive and negative signal transducers to produce a graded response that modulates and, ultimately, terminates B-cell receptor (BCR) signaling (Cyster and Goodnow, 1997). While signalosome activation events have been relatively well characterized, the events important for negative regulation of BCR signaling remain elusive.Bruton's tyrosine kinase (Btk) plays a pivotal role in the regulation of pre-B and mature BCR signaling, and is a major component of the BCR signalosome (Fruman et al., 2000;Guo et al., 2000). Mutation of Btk results in X-linked agammaglobulinemia (XLA) in humans and X-linked immunode®ciency (xid) in mice. These diseases are associated with impaired maturation of B cells, diminished immunoglobulin production, compromised T-independent immune response and marked attenuation of the sustained calcium signal upon BCR stimulation (Rawlings, 1999). Btk contains an N-terminal Pleckstrin homology (PH) domain, followed by Tec homology (TH), SH3, SH2 and kinase dom...

The lipoxygenase (LO) pathway of arachidonate metabolism and mitogen-activated protein kinases (MAPKs) can mediate cellular growth and ANG II effects in vascular smooth muscle cells. However, their role in renal mesangial cells (MC) is not very clear. ANG II treatment of rat MC significantly increased 12-LO mRNA expression and formation of the 12-LO product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE; P < 0.03]. ANG II-induced [(3)H]leucine incorporation was blocked by an LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (P < 0.02). 12(S)-HETE and ANG II directly induced cellular hypertrophy and fibronectin (FN) expression (P < 0.01) to a similar extent. ANG II and 12(S)-HETE led to activation of p38(MAPK) and its target transcription factor cAMP-responsive element-binding protein (CREB). ANG II- and 12(S)-HETE-induced CREB activation and [(3)H]leucine incorporation were blocked by the p38(MAPK) inhibitor SB-202190. A specific molecular inhibitor of rat 12-LO mRNA, namely, a novel ribozyme, could attenuate ANG II-induced FN mRNA. Thus p38(MAPK)-dependent CREB activation may mediate ANG II- and LO product-induced FN expression and cellular growth in rat MC. ANG II effects may be mediated by the LO pathway. These results suggest a novel interaction between LO and p38(MAPK) activation in MC matrix synthesis associated with renal complications.

Background and AimsMesangial C3 deposition is frequently observed in patients with IgA nephropathy (IgAN). However, the role of complement in the pathogenesis or progression of IgAN is uncertain. In this observational cohort study, we aimed to identify the clinical implications of circulating C3 levels and mesangial C3 deposition and to investigate their utility as predictors of renal outcomes in patients with IgAN.MethodsA total of 343 patients with biopsy-proven IgAN were enrolled between January 2000 and December 2008. Decreased serum C3 level (hypoC3) was defined as C3 <90 mg/dl. The study endpoint was end-stage renal disease (ESRD) and a doubling of the baseline serum creatinine (D-SCr).ResultsOf the patients, there were 66 patients (19.2%) with hypoC3. During a mean follow-up of 53.7 months, ESRD occurred in 5 patients (7.6%) with hypoC3 compared with 9 patients (3.2%) with normal C3 levels (P = 0.11). However, 12 patients (18.2%) with hypoC3 reached D-SCr compared with 17 patients (6.1%) with normal C3 levels [Hazard ratio (HR), 3.59; 95% confidence interval (CI), 1.33–10.36; P = 0.018]. In a multivariable model in which serum C3 levels were treated as a continuous variable, hypoC3 significantly predicted renal outcome of D-SCr (per 1 mg/dl increase of C3; HR, 0.95; 95% CI, 0.92–0.99; P = 0.011). The risk of reaching renal outcome was significantly higher in patients with mesangial C3 deposition 2+ to 3+ than in patients without deposition (HR 9.37; 95% CI, 1.10–80.26; P = 0.04).ConclusionsThis study showed that hypoC3 and mesangial C3 deposition were independent risk factors for progression, suggesting that complement activation may play a pathogenic role in patients with IgAN.

Our study demonstrates that RDW could be an additive predictor for all-cause mortality in AKI patients on CRRT treatment in the ICU.

The data were presented in abstract form at the 45th meeting of the American Society of Nephrology, October 30-November 04 2012, San Diego, CA, USA. Circulating autoantibodies against M-type phospholipase A2 receptor (PLA2R) are important pathogenic antibodies of idiopathic membranous nephropathy (MN) in adults. However, previous studies on the clinical impact of anti-PLA2R antibodies demonstrated several limitations, including insufficient numbers of study subjects and different time points and methods for anti-PLA2R antibody measurement. To verify the clinical significance of anti-PLA2R antibodies in Korean patients with MN, we measured autoantibodies in serum samples obtained at the time of biopsy from a total of 100 patients with idiopathic MN who had not yet received immunosuppressive treatment. We detected anti-PLA2R antibody in 69 patients, and we observed that autoantibody reactivity reflected the severity of disease activity. Proteinuria and hypoalbuminemia were more severe in patients with anti-PLA2R than in those without the autoantibodies (2.95 g/g vs. 6.85 g/g, P = 0.003; 3.1 g/dL vs. 2.5 g/dL, P = 0.004, respectively). Additionally, the clinical severities worsened proportionally as the levels of anti-PLA2R antibodies increased (P = 0.015 and P for trend <0.001 for proteinuria and hypoalbuminemia, respectively). However, neither the levels nor the presence or absence of anti-PLA2R antibody showed a significant correlation with clinical outcomes, such as remission rate and time to remission. In conclusion, we observed that anti-PLA2R antibodies are highly prevalent in Korean patients with idiopathic MN and that they reflect the clinical disease activity before the administration of immunosuppressive treatment. However, the levels of anti-PLA2R antibody at the time of kidney biopsy may not predict the clinical outcomes in current clinical practice.

Objective To evaluate the predictive value of a single baseline serum C-reactive protein (sCRP) as a marker of mortality in continuous ambulatory peritoneal dialysis (CAPD) patients. Design A review of prospectively collected data in a 2-year follow-up study. Setting Tertiary medical center. Patients The study included 106 patients who were stable and had been on CAPD for a minimum of 3 months. Main Outcome Measures Patient survival rate was the main outcome measure of this study. Other outcome measures were technique survival rate, peritonitis rate, and hospitalized days. Covariables used in the survival analysis were age, sex, the presence of cardiovascular disease or diabetes mellitus, sCRP, serum albumin, hematocrit, cholesterol, HDL-cholesterol, malnutrition by subjective global assessment (SGA), weekly Kt/V urea, and weekly standardized creatinine clearance (SCCr). Results The 2-year patient survival rate was significantly lower in the increased sCRP group than in the normal sCRP group (66.7% vs 94.1%, p = 0.001), although there was no significant difference in technique failure, peritonitis rate, and hospitalized days between the two groups. By Cox proportional hazards analysis, independent predictors of mortality were: cardiovascular disease (relative risk, RR = 8.96, p < 0.005); increased sCRP level (RR = 1.19, p < 0.05); and high hematocrit (RR = 1.18, p < 0.05). ← Conclusion Serum CRP at enrollment is an independent predictor of 2-year patient survival in CAPD patients.