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Ischaemia-reperfusion injury is a common occurrence in renal transplantation and may affect the long-term survival of the allograft. Oxidative stress may play a crucial role in this, with reactive oxygen species formed during reperfusion causing direct cellular damage as well as activating pro-inflammatory pathways. A human proximal tubule cell line (HK-2) was subjected to hydrogen peroxide (H(2)O(2)) stress that resulted in phosphorylation of c-jun N-terminal kinases (JNKs) and the transcription factor NF-kappaB at Ser276, both of which have been associated with inflammation. Interleukin (IL)-8 production also increased upon H(2)O(2) stimulation. Pre-incubation of the cells with mycophenolic acid (MPA) resulted in reduced phosphorylation of both JNKs and NF-kappaB, and reduced IL-8 release in H(2)O(2)-stimulated HK-2 cells. MPA also reduced the H(2)O(2)-induced phosphorylation of p38 MAP (mitogen-activated protein) kinase, the extracellular-signal regulated kinase 1/2 (ERK1/2), Akt kinase and the transcription factor CREB (cyclic AMP response element binding protein). In rat kidneys subjected to ischaemia-reperfusion, an increase in both pJNK1/2 and pNF-kappaB was observed, which was reduced in kidneys obtained from mycophenolate mofetil (MMF)-treated rats. These results suggest that MPA may inhibit pro-inflammatory responses in the kidney by inhibiting activation of pro-inflammatory molecules in both the kidney and human renal proximal tubular cells subjected to oxidative stress.

Role of different dialysis membranes in the release of interleukin-6-soluble receptor in uremic patients.BackgroundInterleukin-6 (IL-6) exerts its actions through a cell-surface receptor system that consists of two transmembrane subunits: the IL-6 binding glycoprotein gp 80 (IL-6R) and the signal-transducing component (gp 130). Soluble forms of the IL-6R (sIL-6R) are generated by shedding of the membrane-associated proteins. The sIL-6R binds the ligand IL-6 with comparable affinity as the membrane-associated IL-6R and enhances the actions of IL-6.MethodsOur aim was to evaluate the role of both uremia and different dialysis membranes on peripheral blood mononuclear cell (PBMC) release (either in absence or in presence of mitogen stimulation) and plasma levels of sIL-6R. Ten patients chronically dialyzed with cuprophan membranes (CU), eight patients on regular dialysis treatment with polymethylmethacrylate (PMMA) membranes, 11 uremic nondialyzed patients (UR), and 12 healthy subjects (CON) were included in the study.ResultsPBMCs harvested from CU spontaneously released significantly (P < 0.01) greater amounts of sIL-6R (881.8 ± 80.1 pg/mL), as compared with CON (267.5 ± 26.5 pg/mL), UR (258.4 ± 38.1 pg/mL), and PMMA (288.4 ± 24.6 pg/mL). Under mitogenic stimulation, the sIL-6R release was significantly (P < 0.01) increased in all groups. The greater PBMC production of sIL-6R in CU was followed by significantly (P < 0.01) higher levels of circulating soluble receptors (48.7 ± 2.5 ng/mL, 60%), as compared with CON (30.5 ± 1.9 ng/mL). UR also showed high circulating levels of sIL-6R (53.3 ± 5.9 ng/mL), probably secondary to an impaired urinary excretion. Circulating levels of sIL-6R in PMMA were comparable to CON (30.3 ± 3.3 ng/mL). Either the absence of monocyte activation or the adsorption of sIL-6R on the hydrophobic PMMA surface could explain this finding.ConclusionsThese results suggest an important role for poor dialysis biocompatibility of CU on the release of sIL-6R, which increases sIL-6R plasma levels, thereby enhancing the inflammatory effects of IL-6.