Shiga toxin has the potential to induce expression of inflammation-associated genes, although the underlying mechanisms are not well understood. We examined the effects of subtilase cytotoxin (SubAB), an AB5 toxin produced by some Shiga toxigenic Escherichia coli, on the activation of NF-κB. SubAB is known to be a protease which selectively degrades GRP78/Bip. Treatment of NRK-52E cells with SubAB caused rapid cleavage of GRP78. Following the degradation of GRP78, transient activation of NF-κB was observed with a peak at 6–12 h; the activation subsided within 24 h despite the continuous absence of intact GRP78. The activation of NF-κB was preceded by transient phosphorylation of Akt. Treatment of the cells with a selective inhibitor of Akt1/2 or an inhibitor of PI3K attenuated SubAB-induced NF-κB activation, suggesting that activation of Akt is an event upstream of NF-κB. Degradation of GRP78 caused the unfolded protein response (UPR), and inducers of the UPR mimicked the stimulatory effects of SubAB on Akt and NF-κB. SubAB triggered the three major branches of the UPR including the IRE1-XBP1, PERK, and ATF6 pathways. Dominant-negative inhibition of IRE1α, XBP1, or PERK did not attenuate activation of NF-κB by SubAB. In contrast, genetic and pharmacological inhibition of ATF6 significantly suppressed SubAB-triggered Akt phosphorylation and NF-κB activation. These results suggested that loss of GRP78 by SubAB leads to transient phosphorylation of Akt and consequent activation of NF-κB through the ATF6 branch of the UPR.

Focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that is characterized by progressive proteinuria and declining renal function. Secondary FSGS is known to be associated with various diseases. However, an association of FSGS with essential thrombocythemia (ET) has been reported in few cases. We report a 76-year-old man who presented with nephrotic syndrome and hepatosplenomegaly. He had thrombocythemia after a splenectomy, which had been carried out at a nearby hospital. A renal biopsy showed that he had focal segmental glomerulosclerosis (FSGS), while assessment of the bone-marrow specimen revealed that he had ET. A possible relationship between FSGS, which occurred in association with a dramatic increase of thrombocytes after a splenectomy in a patient with ET, and increased serum levels of transforming growth factor (TGF)-beta, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF)-BB was suggested.

These results indicate a role for the acidic stress-ER stress pathway in blunted activation of NF-κB, which may cause perturbation of monocyte recruitment by mesothelial cells in PD patients.

These results suggest a possibility that mesothelial cells exposed to PDF exhibit attenuated MCP-1 expression and consequent impairment of macrophage recruitment through dual mechanisms, that is, inhibition of NF-κB by acidic stress and blunted activation of p38 MAP kinase by osmotic stress. In patients on peritoneal dialysis, blunted expression of chemokines may lead to perturbation of bacterial clearance by macrophages in the peritoneal cavity.

In patients with end-stage renal disease, renal anemia develops as a result of erythropoietin deficiency. Recombinant human erythropoietin(rHuEPO)has been widely prescribed to treat renal anemia. Darbepoetin, which is an analogue of rHuEPO with an increased terminal half-life, has been approved in Japan since July 2007. We performed a prospective study to compare Hb-maintenance dose and cost effectiveness between darbepoetin and rHuEPO in hemodialysis patients for 18 weeks. Our cohort comprised 77 patients who were undergoing maintenance hemodialysis 3 times per week in Suzuki-Nephro Clinic. The patients were divided into ／ two groups. Thirty-nine patients were assigned to receive rHuEPO 750 IU／HD and 39 patients were assigned ／ ／ darbepoetin 15 mg／week as Hb-maintenance dose to maintain a target Hb level of 10.0 to 11.4 g／dL, respectively. At 18 weeks, the mean Hb level of darbepoetin group was significantly higher than that of rHuEPO group. The proportion of patients whose Hb level exceeded target Hb level was significantly higher in the darbepoetin group than rHuEPO group. Although final Hb level was higher in darbepoetin group than that of rHuEPO group, the cost