Editorial: Kidney Transplantation and Innate Immunity

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Transforming growth factor-β1 regulates chemokine and complement production by human proximal tubular epithelial cells

Transforming growth factor-γ1 regulates chemokine and complement production by human proximal tubular epithelial cells. Previously it has been demonstrated that human proximal tubular epithelial cells (PTEC) are able to produce chemokines (such as IL-8 and MCP-1) and complement components (such as C2, C3, C4 and factor H), and that production of these proteins is regulated by pro-inflammatory cytokines such as interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Since TGF-γ is also expressed in the renal interstitium during inflammation, we investigated the effect of TGF-γ on the production of chemokines and complement components by PTEC in culture. Transforming growth factor-γ1 up-regulated IL-8 production by an average of 4.11 ± 1.0-fold. macrophage chemoattractant phagocyte (MCP-1) production, on the other hand, was down-regulated by TGF-γ1 by an average of 2.2 ± 0.7-fold. The production of C3 and C4 was also down-regulated after incubation with TGF-γ1 (1.9 ± 0.3- and 3.0 ± 1.2-fold, respectively). All effects were dose- and time-dependent and were found to be specific for TGF-γ1, as assessed by inhibition of the effect with a neutralizing antibody against TGF-γ1. These data, together with the knowledge that TGF-γ, chemokines and complement components play a role in several types of renal disease, suggest that TGF-γ is involved in the regulation of local expression of chemokines and complement components by tubular cells

Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-β1

Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-β1.BackgroundVarious renal cell types have been shown to contribute to the excessive matrix deposition observed in diabetic nephropathy. The present study examined the effect of high ambient glucose and transforming growth factor-β1 (TGF-β1) on matrix production by human renal fibroblasts.MethodsHuman renal fibroblasts (TK173) were used to examine the effects of high glucose and TGF-β1 on fibronectin and collagen type III expression. Stable transfectants were generated of TK173 cells expressing a dominant negative TGF-β type II receptor. Matrix components were measured in enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR).ResultsFibronectin secretion by renal fibroblasts was increased upon exposure to high glucose, but with delayed kinetics compared to TGF-β1-induced fibronectin. Exposure to high glucose resulted in an increased secretion of latent TGF-β1. However, treatment with neutralizing pan-specific anti-TGF-β antibodies could not attenuate the effects of glucose. Furthermore, collagen type III was up-regulated by high glucose, but not by TGF-β1. Importantly, fibroblasts expressing a dominant negative TGF-β type II receptor were defective in TGF-β1-induced fibronectin production, whereas glucose-induced fibronectin and collagen type III were unaffected.ConclusionsThese data show that in renal fibroblasts exposure to high glucose can increase matrix production independent of endogenous TGF-β1. Although glucose activation is accompanied by an increased production of latent TGF-β1, which can have an important role in vivo, the data suggest involvement of alternative growth factors in the mechanism by which hyperglycemic conditions can modulate matrix accumulation in diabetic nephropathy

Effect of Taste Enhancement on Consumer Acceptance of Pureed Cucumber and Green Capsicum

Abstract: Vegetables have low taste intensities, which might contribute to low acceptance. The aim of this study was to investigate the effect of taste (sweetness, sourness, bitterness, umami, and saltiness) and fattiness enhancement on consumer acceptance of cucumber and green capsicum purees. Three concentrations of sugar, citric acid, caffeine, mono-sodium glutamate, NaCl, and sunflower oil were added to pureed cucumber and green capsicum. Subjects (n = 66, 35.6 ± 17.7 y) rated taste and fattiness intensity. Different subjects (n = 100, 33.2 ± 16.5 years) evaluated acceptance of all pureed vegetables. Taste intensities of vegetable purees were significantly different (P < 0.05) between the three tastant concentrations except for umami in both vegetable purees, sourness in green capsicum puree, and fattiness in cucumber puree. Only enhancement of sweetness significantly (P < 0.05) increased acceptance of both vegetable purees compared to unmodified purees. In cucumber purees, relatively small amounts of added sucrose (2%) increased acceptance already significantly, whereas in green capsicum acceptance increased significantly only with addition of 5% sucrose. Enhancement of other taste modalities did not significantly increase acceptance of both vegetable purees. Enhancing saltiness and bitterness significantly decreased acceptance of both vegetable purees. We conclude that the effect of taste enhancement on acceptance of vegetable purees differs between tastants and depends on tastant concentration and vegetable type. With the exception of sweetness, taste enhancement of taste modalities such as sourness, bitterness, umami, and saltiness was insufficient to increase acceptance of vegetable purees. We suggest that more complex taste, flavor, or texture modifications are required to enhance acceptance of vegetables. Practical Application: Results can be used by cultivators to select and grow vegetable varieties with enhanced taste and flavor. Especially for cucumber, relatively small sweetness enhancement is sufficient to increase acceptance.</p

Mannan-binding lectin is involved in the protection against renal ischemia/ reperfusion injury by dietary restriction

Preoperative fasting and dietary restriction offer robust protection against renal ischemia/ reperfusion injury (I/RI) in mice.We recently showed that Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, plays a pivotal role in renal I/RI. Based on these findings, we investigated the effect of short-term DR (30% reduction of total food intake) or three days of water only fasting on MBL in 10-12 weeks old male C57/Bl6 mice. Both dietary regimens significantly reduce the circulating levels of MBL as well as its mRNA expression in liver, the sole production site of MBL. Reconstitution of MBL abolished the protection afforded by dietary restriction, whereas in the fasting group the protection persisted. These data show that modulation of MBL is involved in the protection against renal I/RI induced by dietary restriction, and suggest that the mechanisms of protection induced by dietary restriction and fasting may be different. Copyright

Peripheral Blood Immune Cell Composition After Autologous MSC Infusion in Kidney Transplantation Recipients

Tacrolimus is the backbone of immunosuppressive agents to prevent transplant rejection. Paradoxically, tacrolimus is nephrotoxic, causing irreversible tubulointerstitial damage. Therefore, infusion of mesenchymal stromal cells (MSC) 6 and 7 weeks post-transplantation was assessed to facilitate withdrawal of tacrolimus in the randomized phase II TRITON trial. Here, we performed detailed analysis of the peripheral blood immune composition using mass cytometry to assess potential effects of MSC therapy on the immune system. We developed two metal-conjugated antibody panels containing 40 antibodies each. PBMC samples from 21 MSC-treated patients and 13 controls, obtained pre-transplant and at 24 and 52 weeks post-transplantation, were analyzed. In the MSC group at 24 weeks, 17 CD4+ T cell clusters were increased of which 14 Th2-like clusters and three Th1/Th2-like clusters, as well as CD4+FoxP3+ Tregs. Additionally, five B cell clusters were increased, representing either class switched memory B cells or proliferating B cells. At 52 weeks, CCR7+CD38+ mature B cells were decreased. Finally, eight Tc1 (effector) memory cytotoxic T cell clusters were increased. Our work provides a comprehensive account of the peripheral blood immune cell composition in kidney transplant recipients after MSC therapy and tacrolimus withdrawal. These results may help improving therapeutic strategies using MSCs with the aim to reduce the use of calcineurin inhibitors. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02057965.</p

Different selectivities of oxidants during oxidation of methionine residues in the α-1-proteinase inhibitor

AbstractOxidation of the reactive site methionine (Met) in α-1-proteinase inhibitor (α-1-PI) to methionine sulfoxide (Met(O)) is known to cause depletion of its elastase inhibitory activity. To estimate the selectivity of different oxidants in converting Met to Met(O) in α-1-PI, we measured the molar ratio Met(O)/α-1-PI at total inactivation. This ratio was determined to be 1.2 for both the myeloperoxidase/H2O2/chloride system and the related compound NH2Cl. With taurine monochloramine, another myeloperoxidase-related oxidant, 1.05 mol Met(O) were generated per mol α-1-PI during inactivation. These oxidants attack preferentially one Met residue in α-1-PI, which is identical with Met 358, as concluded from the parallelism of loss of elastase inhibitory activity and oxidation of Met. A similar high specificity for Met oxidation was determined for the xanthine oxidase-derived oxidants. In contrast, the ratio found for ozone and m-chloroperoxybenzoic acid was 6.0 and 5.0, respectively, indicating oxidation of additional Met residues besides the reactive site Met in α-1-PI, i.e. unselective action of these oxidants. Further studies were performed on the efficiency of oxidants for total depletion of the elastase inhibitory capacity of α-1-PI. Ozone and m-chloroperoxybenzoic acid were 10-fold less effective and the superoxide anion/hydroxyl radicals were 30–50-fold less effective to inactivate the elastase inhibitory activity as compared to the myeloperoxidase-derived oxidants. The myeloperoxidase-related oxidants are discussed as important regulators of α-1-PI activity in vivo