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• W2045018966 abstract "Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation. Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation. Chronic kidney disease is the ninth leading cause of death in the United States accounting for over 40,000 deaths annually.1.Kung H.C. Hoyert D.L. Xu J. et al.Deaths: final data for 2005.Natl Vital Stat Rep. 2008; 56: 1-120PubMed Google Scholar Despite advances in renal replacement therapy, transplantation remains the preferred treatment for suitable candidates.2.Wolfe R.A. Ashby V.B. Milford E.L. et al.Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant.N Engl J Med. 1999; 341: 1725-1730Crossref PubMed Scopus (3581) Google Scholar However, in spite of improved postoperative immunosuppression regimens, the 10-year graft survival rates are 55 and 75% for cadaveric and live donor kidney allografts, respectively. The vast majority of late failures are attributable to chronic allograft nephropathy (CAN), recently reclassified as interstitial fibrosis and tubular atrophy with unknown etiology.3.Giblin L. O’Kelly P. Little D. et al.A comparison of long-term graft survival rates between the first and second donor kidney transplanted – the effect of a longer cold ischaemic time for the second kidney.Am J Transplant. 2005; 5: 1071-1075Crossref PubMed Scopus (41) Google Scholar, 4.Gourishankar S. Halloran P.F. Late deterioration of organ transplants: a problem in injury and homeostasis.Curr Opin Immunol. 2002; 14: 576-583Crossref PubMed Scopus (71) Google Scholar, 5.Solez K. Colvin R.B. Racusen L.C. et al.Banff ‘05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’).Am J Transplant. 2007; 7: 518-526Crossref PubMed Scopus (864) Google Scholar, 6.Paul L.C. Chronic allograft nephropathy: an update.Kidney Int. 1999; 56: 783-793Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar The clinical course of CAN is characterized by a progressive deterioration in renal function, manifested by increasing renal hypertension and proteinuria. Presently, no specific treatment is available for chronic rejection in clinical transplantation despite a number of successful approaches in animal models, including the use of macrophage inhibitors, angiotensin converting enzyme inhibitors, and endothelin A receptor antagonists.7.Azuma H. Nadeau K.C. Ishibashi M. et al.Prevention of functional, structural, and molecular changes of chronic rejection of rat renal allografts by a specific macrophage inhibitor.Transplantation. 1995; 60: 1577-1582Crossref PubMed Scopus (68) Google Scholar, 8.Amuchastegui S.C. Azzollini N. Mister M. et al.Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.J Am Soc Nephrol. 1998; 9: 1948-1955PubMed Google Scholar, 9.Azuma H. Binder J. Heemann U. et al.Effects of RS61443 on functional and morphological changes in chronically rejecting rat kidney allografts.Transplantation. 1995; 59: 460-466Crossref PubMed Scopus (121) Google Scholar, 10.Braun C. Conzelmann T. Vetter S. et al.Prevention of chronic renal allograft rejection in rats with an oral endothelin A receptor antagonist.Transplantation. 1999; 68: 739-746Crossref PubMed Scopus (51) Google Scholar A number of factors contribute to the development of CAN, including immunological (for example, acute rejection) and nonimmunological (for example, ischemia-reperfusion injury) factors.11.Tullius S.G. Tilney N.L. Both alloantigen-dependent and -independent factors influence chronic allograft rejection.Transplantation. 1995; 59: 313-318Crossref PubMed Scopus (378) Google Scholar,12.Hayry P. Isoniemi H. Yilmaz S. et al.Chronic allograft rejection.Immunol Rev. 1993; 134: 33-81Crossref PubMed Scopus (208) Google Scholar Oxidative stress is believed to be a common pathway that leads to both immunological and nonimmunological stress in the setting of kidney transplantation and, ultimately, to the development of CAN.13.Djamali A. Oxidative stress as a common pathway to chronic tubulointerstitial injury in kidney allografts.Am J Physiol Renal Physiol. 2007; 293: F445-F455Crossref PubMed Scopus (104) Google Scholar Markers of oxidative stress, such as plasma lipid peroxidases, are increased, whereas antioxidant markers, including glutathione, superoxide dismutase, and glutathione peroxidase, are decreased in the setting of CAN.14.Simic-Ogrizovic S. Simic T. Reljic Z. et al.Markers of oxidative stress after renal transplantation.Transpl Int. 1998; 11: S125-S129Crossref PubMed Scopus (46) Google Scholar, 15.Cristol J.P. Vela C. Maggi M.F. et al.Oxidative stress and lipid abnormalities in renal transplant recipients with or without chronic rejection.Transplantation. 1998; 65: 1322-1328Crossref PubMed Scopus (99) Google Scholar, 16.Gottmann U. Oltersdorf J. Schaub M. et al.Oxidative stress in chronic renal allograft nephropathy in rats: effects of long-term treatment with carvedilol, BM 91.0228, or alpha-tocopherol.J Cardiovasc Pharmacol. 2003; 42: 442-450Crossref PubMed Scopus (23) Google Scholar, 17.Raj D.S. Lim G. Levi M. et al.Advanced glycation end products and oxidative stress are increased in chronic allograft nephropathy.Am J Kidney Dis. 2004; 43: 154-160Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Despite this association, few studies have attempted to examine the effect of antioxidants on kidney allograft outcomes and those that have yielded mixed results. Vitamin E (α-tocopherol) supplementation did not prevent allograft injury in a model of CAN;16.Gottmann U. Oltersdorf J. Schaub M. et al.Oxidative stress in chronic renal allograft nephropathy in rats: effects of long-term treatment with carvedilol, BM 91.0228, or alpha-tocopherol.J Cardiovasc Pharmacol. 2003; 42: 442-450Crossref PubMed Scopus (23) Google Scholar however, in the same model, L-arginine did attenuate proteinuria and glomerulosclerosis.18.Albrecht E.W. van Goor H. Smit-van Oosten A. et al.Long-term dietary L-arginine supplementation attenuates proteinuria and focal glomerulosclerosis in experimental chronic renal transplant failure.Nitric Oxide. 2003; 8: 53-58Crossref PubMed Scopus (24) Google Scholar Furthermore, a clinical trial using recombinant human superoxide dismutase resulted in significantly decreased acute and chronic rejection.19.Land W. Schneeberger H. Schleibner S. et al.The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants.Transplantation. 1994; 57: 211-217Crossref PubMed Scopus (318) Google Scholar Therefore, based on the seemingly conflicting results of these few studies, there is a need for additional investigations into the applicability of antioxidants for the prevention of CAN. Molecular hydrogen has recently been shown to have therapeutic value as an antioxidant through its ability to selectively reduce cytotoxic reactive oxygen species (ROS).20.Ohsawa I. Ishikawa M. Takahashi K. et al.Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.Nat Med. 2007; 13: 688-694Crossref PubMed Scopus (1335) Google Scholar Inhaled hydrogen gas (∼4% H2 in air) can reduce infarct size in rat models of focal cerebral and myocardial ischemia-reperfusion injury.20.Ohsawa I. Ishikawa M. Takahashi K. et al.Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.Nat Med. 2007; 13: 688-694Crossref PubMed Scopus (1335) Google Scholar,21.Hayashida K. Sano M. Ohsawa I. et al.Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury.Biochem Biophys Res Commun. 2008; 373: 30-35Crossref PubMed Scopus (362) Google Scholar More recently, our group reported that perioperative hydrogen inhalation (2%) significantly ameliorates intestinal transplant injury and prevents remote organ inflammation through its antioxidant effects.22.Buchholz B.M. Kaczorowski D.J. Sugimoto R. et al.Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury.Am J Transplant. 2008; 8: 2015-2024Crossref PubMed Scopus (243) Google Scholar Drinking water containing a therapeutic dose of hydrogen (hydrogen water; HW) represents an alternative mode of delivery of molecular hydrogen. The primary advantages of HW are that it is a portable, easily administered, and safe means of delivering molecular hydrogen. Therefore, it may be of potential therapeutic value in the treatment of oxidative stress-induced pathologies. Interestingly, drinking HW, as well as inhaling hydrogen gas, can alleviate cisplatin-induced nephrotoxicity, which is known to be mediated, in part, by the accumulation of ROS that occurs secondary to the ability of cisplatin to inhibit the reducing form of glutathione23.Nakashima-Kamimura N. Mori T. Ohsawa I. et al.Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice.Cancer Chemother Pharmacol. 2009; 64: 753-761Crossref PubMed Scopus (136) Google Scholar Consumption of HW ad libitum prevents the development of atherosclerosis in apolipoprotein E knockout mice, in part, through its ability to limit the amount and deleterious effects of oxidative stress in the blood vessels of these mice.24.Ohsawa I. Nishimaki K. Yamagata K. et al.Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice.Biochem Biophys Res Commun. 2008; 377: 1195-1198Crossref PubMed Scopus (140) Google Scholar Furthermore, a clinical trial in type II diabetic patients given supplemental HW led to improved lipid and glucose metabolism compared with controls.25.Kajiyama S. Hasegawa G. Asano M. et al.Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance.Nutr Res. 2008; 28: 137-143Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar The aim of the present study was to determine the efficacy of HW in preventing CAN after allogeneic kidney transplantation in rats. To determine whether oral administration of HW results in increased local or systemic levels of molecular hydrogen, unoperated naïve Lewis (LEW) rats were given HW to drink and, subsequently, the concentration of molecular hydrogen was measured in the kidney and in the serum. Both local and systemic concentrations of molecular hydrogen peaked ∼15 min after ingestion (Figure 1a), proving that HW is an effective mode of delivery of molecular hydrogen. We also tested whether transplant recipients given long-term, daily HW had increased concentrations of circulating hydrogen. Similar kinetic changes in hydrogen concentration were observed in both LEW recipients with LEW grafts (control rats; syngeneic transplantation prevents CAN) and Brown Norway (BN) recipients with LEW grafts treated with HW for 60 days (Figure 1b). The baseline levels of the hydrogen detected in circulation after 60 days of HW treatment was comparable to that of naïve animals, suggesting that there was no hydrogen accumulation during long-term HW administration. We then sought to determine the effect of HW administration on kidney function after allotransplantation. Isograft recipients (LEW donor and LEW recipient) were included as controls, as these rats do not develop CAN. Using a model of kidney transplantation followed by bilateral nephrectomy, we found that rats receiving daily HW ad libitum had improved allograft function, as measured by blood urea nitrogen, creatinine clearance, and proteinuria, compared with those receiving regular water (RW) at 60 days posttransplantation (Figure 1c). These results suggest that HW can improve kidney function after allotransplantation. To determine whether the improved allograft function that was observed in HW-treated recipients correlated with global parameters of well being, we measured the weights of transplant recipients and found that the majority of animals that had undergone allotransplantation followed by administration of RW began to lose body weight ∼40 days after transplantation. This process was significantly diminished in the allograft recipients that received HW (Figure 2a). Furthermore, we found that weight loss proved to be a harbinger of allograft failure and, ultimately, of death. HW-treated recipients exhibited a significant increase in survival (median survival > 150 days) compared with RW-treated controls (median survival 78 days) (Figure 2b). These results show that the improved allograft function that was observed at 60 days posttransplantation in HW-treated recipients, as compared with RW-treated controls, also leads to improved survival outcomes. To determine whether the improved allograft function and overall survival observed in HW-treated animals were attributable to decreased chronic rejection, histological analysis was performed on allografts obtained 60 days posttransplantation from both RW- and HW-treated recipients. Hematoxylin and eosin staining of the allografts obtained from HW-treated recipients exhibited decreased evidence of the hallmarks of CAN, including less glomerulosclerosis and inflammatory cell infiltration, as compared with hematoxylin and eosin staining of allografts obtained from RW-treated recipients (Figure 3a). Furthermore, Masson's trichrome staining and α-smooth muscle actin (αSMA) staining on allografts obtained from HW-treated recipients showed less interstitial fibrosis and smooth muscle proliferation, respectively, compared with allografts obtained from RW-treated controls (Figure 3b and c). The expression of αSMA, indicating myofibroblast accumulation in the grafts, was mostly seen in the interstitial areas. There was no definitive, αSMA-positive staining in the tubular epithelial cells. Histopathology of the control isografts from the same time point was similar to that of normal naïve animals and was not affected by HW administration (data not shown). In addition, immunohistochemistry for both CD3 and CD68 revealed fewer graft-infiltrating T cells and macrophages, respectively, in allografts obtained from HW-treated recipients compared with those obtained from RW-treated controls (Figure 4a and b). These results proved to be statistically significant when the number of positive-staining cells per high-power field was counted for each sample (Figure 4c). Taken in total, these histological results suggest that allografts from HW-treated recipients experienced less CAN than did those from RW-treated controls.Figure 4Hydrogen water (HW) administration decreases intragraft inflammatory cell infiltration after kidney allotransplantation. CD3-positive (a) and CD68-positive (b) infiltrating cells were assessed by immunohistochemistry and quantitated as number of positive-staining cells per high-power field (HPF) (original magnification × 400) (c). Images are representative of five individual animals for each group; (n=5 for each group, original magnification × 200, *P<0.05 versus Allo/RW). Allo/HW, allograft given HW; Allo/RW, allograft given RW; Iso HW, isograft given HW; Iso RW, isograft given RW; RW, regular water.View Large Image Figure ViewerDownload (PPT) As mentioned previously, molecular hydrogen possesses potent antioxidant properties. Furthermore, oxidant stress-induced tissue damage is believed to be a common pathway in many of the pathophysiological mechanisms involved in the development of CAN. Therefore, owing to the fact that HW administration resulted in increased local and systemic concentrations of molecular hydrogen, as well as decreased histological evidence of CAN in kidney allograft recipients compared with RW-treated controls, we next determined whether the protection from CAN seen with HW administration was accompanied by a decrease in markers of oxidative tissue injury. Tissue malondialdehyde (MDA) levels, which indicate lipid peroxidation in cells and tissues, were significantly decreased in allografts obtained 60 days posttransplantation from HW-treated recipients compared with those obtained from RW-treated controls (Figure 5a). Furthermore, immunohistochemistry performed on allografts obtained from HW-treated recipients exhibited less 4-hydroxy-2-nonenal (HNE) and peroxynitrite staining compared with that seen in allografts obtained from RW-treated controls (Figure 5b and c). These results show that the local and systemic levels of molecular hydrogen that are achieved through the administration of HW are sufficient to effectively reduce oxidative stress-induced tissue damage in the setting of kidney allotransplantation. One mechanism by which oxidative stress leads to the development of chronic rejection is by increasing the production of inflammatory cytokines.26.Lloberas N. Torras J. Herrero-Fresneda I. et al.Postischemic renal oxidative stress induces inflammatory response through PAF and oxidized phospholipids. Prevention by antioxidant treatment.FASEB J. 2002; 16: 908-910PubMed Google Scholar,27.Cho M. Hunt T.K. Hussain M.Z. Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release.Am J Physiol Heart Circ Physiol. 2001; 280: H2357-H2363PubMed Google Scholar Therefore, because HW administration led to decreased oxidative stress and slowed the progression toward CAN in kidney allografts, we next determined whether HW treatment was also associated with a decrease in local inflammatory cytokine production. Quantitative reverse transcription PCR revealed significantly lower levels of interleukin-6, tumor necrosis factor-α, intracellular adhesion molecule-1, and interferon-γ mRNA in kidney allografts obtained from HW-treated recipients 60 days posttransplantation as compared with those obtained from RW-treated controls (Figure 6a–d). These results indicate that HW administration can attenuate the local production of inflammatory markers in the setting of kidney allotransplantation. Inflammatory intracellular signaling pathway activation (most notably activation of mitogen-activated protein kinases; MAP kinases) is a well-described event that contributes to the progression of kidney allografts toward chronic rejection.28.Park J. Ha H. Seo J. et al.Mycophenolic acid inhibits platelet-derived growth factor-induced reactive oxygen species and mitogen-activated protein kinase activation in rat vascular smooth muscle cells.Am J Transplant. 2004; 4: 1982-1990Crossref PubMed Scopus (50) Google Scholar, 29.Ha H. Kim M.S. Park J. et al.Mycophenolic acid inhibits mesangial cell activation through p38 MAPK inhibition.Life Sci. 2006; 79: 1561-1567Crossref PubMed Scopus (29) Google Scholar, 30.Wada T. Azuma H. Furuichi K. et al.Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase.Am J Nephrol. 2006; 26: 319-325Crossref PubMed Scopus (13) Google Scholar Oxidative stress can activate MAP kinase signaling, which ultimately contributes to the proliferation of mesangial cells in the setting of diabetic nephropathy.31.Dentelli P. Rosso A. Zeoli A. et al.Oxidative stress-mediated mesangial cell proliferation requires RAC-1/reactive oxygen species production and beta4 integrin expression.J Biol Chem. 2007; 282: 26101-26110Crossref PubMed Scopus (22) Google Scholar Mesangial cell proliferation is also involved in the development of CAN. Therefore, we next determined whether HW administration could suppress MAP kinase activation in the kidney allografts. Western blot analysis showed that MAP kinases, including c-Jun N-terminal kinase, p-38, extracellular signal-regulated protein kinase as well as upstream kinase cascades (MEK-1), were less activated in allografts obtained from HW-treated recipients than in allografts obtained from RW-treated recipients (Figure 7). These results indicate that HW administration can inhibit intracellular signaling pathways that are known to contribute to the development of CAN in the setting of kidney transplantation (Supplemental data). In this study, we found that both allograft function and overall survival were improved in rats that had been fed with a diet supplemented with HW. Allografts from HW-treated rats exhibited less infiltration of inflammatory cells and suppressed activation of intragraft inflammatory signaling pathways. The allografts from the HW-treated rats manifested fewer markers of oxidative stress and, ultimately, fewer progressed toward CAN as compared with controls. These results indicate that HW represents a potentially novel therapeutic strategy in the prevention of CAN in kidney transplantation. Molecular hydrogen is produced continuously under normal physiological conditions, primarily during the fermentation of nondigestible carbohydrates by intestinal bacteria in the large intestine. This physiological production of hydrogen gas may be responsible for the baseline levels of hydrogen detected in circulation. It is excreted as flatus, further metabolized by gut flora, or exhaled as a natural component of abdominal gas. However, molecular hydrogen has known physiological roles during conditions of homeostasis. Recent evidence indicates that inhaled hydrogen gas has antioxidant and anti-apoptotic properties that can protect organs from ischemia-reperfusion-induced injury by selectively scavenging detrimental ROS. The mechanism of action of inhaled hydrogen gas in these models involves its ability to prevent oxidative damage, as indicated by decreased nucleic acid oxidation and lipid peroxidation.20.Ohsawa I. Ishikawa M. Takahashi K. et al.Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.Nat Med. 2007; 13: 688-694Crossref PubMed Scopus (1335) Google Scholar,21.Hayashida K. Sano M. Ohsawa I. et al.Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury.Biochem Biophys Res Commun. 2008; 373: 30-35Crossref PubMed Scopus (362) Google Scholar Although the concentration of gaseous molecular hydrogen used in the above studies (∼4%) is lower than the threshold at which it is known to be flammable (4.6%), flammability is still a realistic concern which may limit the translational applicability of inhaled molecular hydrogen. Therefore, HW represents a novel and easily translatable method of delivery of molecular hydrogen. To our knowledge, this is the first report describing the preventative effects of molecular hydrogen, delivered in water containing therapeutic doses, on the development of chronic rejection in the setting of kidney allotransplantation and, as such, represents a potentially novel and easily applicable solution to a difficult clinical scenario (that is, CAN). The major novel findings of the present study are that (i) HW improves allograft function and overall survival by preventing CAN in a rodent model of kidney transplantation, doing so in part by (ii) reducing oxidative stress-induced damage and (iii) reducing the activation of inflammatory signaling pathways and cytokine production. The basis for the present study was the fact that oxidative stress is believed to be a common pathway that leads to the development of chronic rejection in kidney transplantation. As mentioned earlier, markers of oxidative stress are elevated in kidney transplant recipients and, in contrast, markers of antioxidant pathways are diminished. Mechanistically, ROS activate inflammatory intracellular signaling pathways in vascular smooth muscle cells,28.Park J. Ha H. Seo J. et al.Mycophenolic acid inhibits platelet-derived growth factor-induced reactive oxygen species and mitogen-activated protein kinase activation in rat vascular smooth muscle cells.Am J Transplant. 2004; 4: 1982-1990Crossref PubMed Scopus (50) Google Scholar induce the epithelial-to-mesenchymal transition,32.Rhyu D.Y. Yang Y. Ha H. et al.Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells.J Am Soc Nephrol. 2005; 16: 667-675Crossref PubMed Scopus (424) Google Scholar,33.Djamali A. Reese S. Yracheta J. et al.Epithelial-to-mesenchymal transition and oxidative stress in chronic allograft nephropathy.Am J Transplant. 2005; 5: 500-509Crossref PubMed Scopus (90) Google Scholar participate in extracellular matrix deposition by mesangial cells,34.Jiang Z. Seo J.Y. Ha H. et al.Reactive oxygen species mediate TGF-beta1-induced plasminogen activator inhibitor-1 upregulation in mesangial cells.Biochem Biophys Res Commun. 2003; 309: 961-966Crossref PubMed Scopus (96) Google Scholar and contribute to renal tubular atrophy through apoptosis35.Allen D.A. Harwood S. Varagunam M. et al.High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases.FASEB J. 2003; 17: 908-910Crossref PubMed Scopus (187) Google Scholar,36.Djamali A. Reese S. Oberley T. et al.Heat shock protein 27 in chronic allograft nephropathy: a local stress response.Transplantation. 2005; 79: 1645-1657Crossref PubMed Scopus (42) Google Scholar and inflammation26.Lloberas N. Torras J. Herrero-Fresneda I. et al.Postischemic renal oxidative stress induces inflammatory response through PAF and oxidized phospholipids. Prevention by antioxidant treatment.FASEB J. 2002; 16: 908-910PubMed Google Scholar,27.Cho M. Hunt T.K. Hussain M.Z. Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release.Am J Physiol Heart Circ Physiol. 2001; 280: H2357-H2363PubMed Google Scholar—all of which are key processes involved in the pathogenesis of CAN. Given the association described above between oxidative stress and the development of CAN, the finding that HW administration effectively decreases the intragraft accumulation of markers of oxidative stress, such as MDA, 4-HNE, and peroxynitrite, suggests that the antioxidant properties of molecular hydrogen are likely to be responsible for the beneficial effects on the allograft function and the prevention of progression of CAN that were observed in this rat model of kidney allotransplantation. We examined the intragraft expression of tumor necrosis factor-α, interleukin-6, interferon-γ, and intracellular adhesion molecule-1 at the mRNA level, as surrogate markers of the deleterious processes downstream from oxidative damage, and found less expression of these inflammatory cytokines in HW-treated recipients, which are well-described mediators of the fibrogenesis phase of CAN.37.Mannon R.B. Therapeutic targets in the treatment of allograft fibrosis.Am J Transplant. 2006; 6: 867-875Crossref PubMed Scopus (66) Google Scholar Furthermore, MAP kinase signaling, which is known to be induced by oxidative damage in the setting of kidney transplantation, was decreased in HW-treated recipients. MAP kinase signaling contributes to the development of CAN by mediating the action of growth factors, such as transforming growth factor-β,38.Wang S. Jiang J. Guan Q. et al.Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling.Am J Physiol Renal Physiol. 2008; 295: F672-F679Crossref PubMed Scopus (8) Google Scholar participating in the proliferation of vascular smooth muscle cells28.Park J. Ha H. Seo J. et al.Mycophenolic acid inhibits platelet-derived growth fa" @default.
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• W2045018966 title "Oral hydrogen water prevents chronic allograft nephropathy in rats" @default.
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