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• W2033133023 abstract "Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia–reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans. Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia–reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans. Renal ischemia–reperfusion injury (IRI) still represents a major clinical complication after both transplantation and renal surgery.1.El-Zoghby Z.M. Stegall M.D. Lager D.J. et al.Identifying specific causes of kidney allograft loss.Am J Transplant. 2009; 9: 527-535Crossref PubMed Scopus (548) Google Scholar Although advanced surgical techniques, novel immunosuppressive regimens, and more effective prophylaxis of infections resulted in markedly improved outcomes, 2–50% of all kidney transplants still manifest some degree of early dysfunction, leading to the clinical syndrome of delayed graft function.2.Perico N. Cattaneo D. Sayegh M.H. et al.Delayed graft function in kidney transplantation.Lancet. 2004; 364: 1814-1827Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar This form of acute renal failure3.Sharfuddin A.A. Sandoval R.M. Berg D.T. et al.Soluble thrombomodulin protects ischemic kidneys.J Am Soc Nephrol. 2009; 20: 524-534Crossref PubMed Scopus (97) Google Scholar (ARF) following ischemia and reperfusion results in post-transplantation oliguria, increased allograft immunogenicity, and risk of acute rejection episodes as well as decreased long-term survival.4.Koning O.H. Ploeg R.J. van Bockel J.H. et al.Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. European Multicenter Study Group.Transplantation. 1997; 63: 1620-1628Crossref PubMed Scopus (189) Google Scholar In addition, it has been shown that IRI is also the main cause of ARF after major renal surgery and trauma.5.Nash K. Hafeez A. Hou S. Hospital-acquired renal insufficiency.Am J Kidney Dis. 2002; 39: 930-936Abstract Full Text Full Text PDF PubMed Scopus (1443) Google Scholar, 6.Sharples E.J. Thiemermann C. Yaqoob M.M. Mechanisms of disease: cell death in acute renal failure and emerging evidence for a protective role of erythropoietin.Nat Clin Pract Nephrol. 2005; 1: 87-97Crossref PubMed Scopus (48) Google Scholar, 7.Mehta R.L. Pascual M.T. Soroko S. et al.Spectrum of acute renal failure in the intensive care unit: the PICARD experience.Kidney Int. 2004; 66: 1613-1621Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar IRI entails various pathophysiological events including microcirculatory disorders, endothelial cell activation, and expression of proinflammatory cytokines and adhesion molecules as well as loss of endothelial integrity.8.Bonventre J.V. Weinberg J.M. Recent advances in the pathophysiology of ischemic acute renal failure.J Am Soc Nephrol. 2003; 14: 2199-2210Crossref PubMed Scopus (608) Google Scholar Ischemia and, paradoxically, the reinstitution of blood supply during reperfusion thereby cause not only the resumption of metabolic functions but also the generation of deleterious oxygen-free radicals such as superoxide (O2-), peroxynitrite (ONOO-), and nitric oxide (NO). NO is produced by a family of enzymes called the nitric oxide synthases (NOS) that convert the amino acid L-arginine and O2 to L-citrulline and NO. This NADPH-consuming enzymatic reaction requires Ca2+/calmodulin, flavin adenine dinucleotide, flavin mononucleotide, and heme and tetrahydrobiopterin (BH4) as cofactors. Under physiological conditions, NO has been shown to be an important mediator of vascular homeostasis, inflammation, and neurotransmission.9.Nelson R.J. Demas G.E. Huang P.L. et al.Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase.Nature. 1995; 378: 383-386Crossref PubMed Scopus (524) Google Scholar,10.MacMicking J. Xie Q.W. Nathan C. Nitric oxide and macrophage function.Annu Rev Immunol. 1997; 15: 323-350Crossref PubMed Scopus (3321) Google Scholar NO generation can attenuate renal damage due to inhibition of platelet aggregation and regulation of neutrophil recruitment by inhibiting the expression of adhesion molecules. Moreover, exogenous NO was shown to diminish IRI after solid organ transplantation.11.Benz S. Schnabel R. Weber H. et al.The nitric oxide donor sodium nitroprusside is protective in ischemia/reperfusion injury of the pancreas.Transplantation. 1998; 66: 994-999Crossref PubMed Scopus (27) Google Scholar,12.Ohmori H. Dhar D.K. Nakashima Y. et al.Beneficial effects of FK409, a novel nitric oxide donor, on reperfusion injury of rat liver.Transplantation. 1998; 66: 579-585Crossref PubMed Scopus (54) Google Scholar However, it has also been stated that excessive production of NO predominantly by the inducible NOS isoform can lead to the disruption of active cytoskeleton, thus resulting in proximal tubular cell detachment and tubular obstruction.13.Shoskes D.A. Xie Y. Gonzalez-Cadavid N.F. Nitric oxide synthase activity in renal ischemia-reperfusion injury in the rat: implications for renal transplantation.Transplantation. 1997; 63: 495-500Crossref PubMed Scopus (76) Google Scholar Furthermore, an increase in NO during inflammatory responses has also been linked to neutrophil recruitment, increased production of inflammatory cytokines, and increased ONOO- and O2- formation, both potent oxidants that modify proteins by forming 3-nitrotyrosine.14.Edelstein C.L. Ling H. Schrier R.W. The nature of renal cell injury.Kidney Int. 1997; 51: 1341-1351Abstract Full Text PDF PubMed Scopus (214) Google Scholar Thus, the precise role of NO generated during renal ischemia and reperfusion is discussed controversially and is still under debate. BH4 as an essential NOS cofactor has profound effects on the structure of all NOS isoforms by stabilizing the active dimeric form of the enzyme and increasing substrate affinity. Furthermore, BH4 is highly redox-sensitive and readily oxidized. Oxidative stress induced by IRI has been shown to deplete intracellular BH4 stores below a critical threshold, resulting in an uncoupling of the NOS enzyme after which the heme group can directly reduce oxygen and release superoxide (O2-) instead of NO.13.Shoskes D.A. Xie Y. Gonzalez-Cadavid N.F. Nitric oxide synthase activity in renal ischemia-reperfusion injury in the rat: implications for renal transplantation.Transplantation. 1997; 63: 495-500Crossref PubMed Scopus (76) Google Scholar, 15.Delgado-Esteban M. Almeida A. Medina J.M. Tetrahydrobiopterin deficiency increases neuronal vulnerability to hypoxia.J Neurochem. 2002; 82: 1148-1159Crossref PubMed Scopus (47) Google Scholar, 16.Milstien S. Katusic Z. Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function.Biochem Biophys Res Commun. 1999; 263: 681-684Crossref PubMed Scopus (380) Google Scholar Superoxide in concert with other highly reactive free radicals then form a cytotoxic cocktail capable of initiating inflammatory pathways contributing to IRI.17.Koo D.D. Welsh K.I. West N.E. et al.Endothelial cell protection against ischemia/reperfusion injury by lecithinized superoxide dismutase.Kidney Int. 2001; 60: 786-796Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar The aim of this study was to determine whether BH4 supplementation would exert beneficial effects on IRI in terms of improvement of microvascular perfusion, histological tissue damage, and decrease in the generation of oxygen-free radicals in the kidneys undergoing renal artery clamping. On the basis of our results, we hypothesize that BH4 might be a novel promising therapeutic agent to reduce delayed graft function in kidney transplants as well as ARF after major renal surgery. Total renal biopterin and BH4 tissue levels were assessed by high-performance liquid chromatography. Values are expressed as mean±s.e.m. (n=6 animals per group) in pmol/mg protein. Forty-five minutes of ischemia (I/R) led to a significant decrease in total biopterin levels (45 minI: 12.68±3.77) compared with non-ischemic controls (control: 29.53±3.20; P<0.01). This decrease was maintained throughout the entire observation/reperfusion period (15 minR: 12.47±2.77; 2hR: 12.77±2.11; 7dR: 10.17±1.21; Figure 1a). Treatment with BH4 (I/R+BH4) was associated with a massive increase in kidney biopterin concentrations following 45 min of ischemia (45 min+BH4: 2279±672), as well as after 15 min (15 minR: 2211±441.2) and 2 h (2 hR: 2289±298.7) of reperfusion (P<0.001) (Figure 1b). This confirmed that the administered BH4 reached the kidney during the reperfusion period. The high variability in the I/R+BH4 group was caused by animal-to-animal variation in response to BH4 treatment rather than by variability in the measurement method, which showed a coefficient of variation of 3.1±0.8% (mean±s.d. of triplicate variation of kidney samples of six BH4-treated animals). Following 45 min of ischemia and 120 min of reperfusion, kidneys were analyzed by means of intravital fluorescence microscopy (IVM). To assess and quantify ischemia-induced microvascular injury, functional defects and the potential protective effects of BH4 microcirculatory parameters such as functional capillary density (FCD) and capillary diameter (CD) were determined. FCD is defined as the length of all blood cell-perfused nutritive capillaries per observation area, and CD as the largest distance of two opposite capillary walls per observation area. Forty-five minutes of ischemia (I/R) caused significant perfusion deficits with leakage of the capillary mesh (Figure 2b and d; supplementary online video 1), compared with the homogeneous perfusion patterns of baseline controls (Figure 2a and d; supplementary online video 2). Mean FCD in controls was 429.9±3.33 cm-1, which was significantly decreased after 45 min of warm ischemia (I/R) 376.2±8.10 cm-1 (P<0.01). In parallel, ischemia significantly decreased intercapillary distance (I/R) 2.50±0.08 cm1 compared with controls 4.0±0.13 cm-1 (P<0.01). BH4 administration before ischemia, however, significantly improved all microcirculatory parameters resulting in increased FCD (I/R+BH4) 410.3±2.72 cm-1 (P<0.01) and increased CD (I/R+BH4) 3.63±0.08 cm-1 (P<0.01), comparable with non-ischemic controls (Figure 2c and d; supplementary online video 3).eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0MTFkMWI2ZTk5OTJiNjJjYjUyMmE0YjQ4Y2M1Nzg0NCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjM0NTQ0MTU3fQ.X2ywP8x3l8E0DDZDo3Hk00mz3w-wYKRL-jVOHiCYtwWiyIrTgT5k4IvvGVbO1LH4j66Yb2kR7-wnRnFCqRYpu3PibtnSUKOOCKDWd3ThGB2N2ryh5GpnZYBFCinKbOaifbW3DEjE_NOeN2MkD3axyPjnzwiGuxFMDy2m12zW5k2vP3RYwBszZuimgxlLlQWpcrii6bGFmyCQPKwRyvEcEoSJdQ9R9Zr7ZhxqyzCpIAEGrCSnHOMq_beYelR9s132vsxzJIFHdTtyV9HHG-kiMA9pu_LQFdtdnEZMLfW7A2OvIaxZygmsimlpnYdHt42ZWf5x3HY8Ccy-e6DKQEqTMQ Download .mp4 (0.61 MB) Help with .mp4 files Supplementary online movie 1eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJjNjI5MTc1Y2FhMWJjNjRhNWMwODlhNWI2ZWMzZWRkMiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjM0NTQ0MTU3fQ.RKTfoigeGOzBdvlTPpf5X61fWgAvq1KrSEk6HLxcwrvkQ7LFQRYIh_Y1fj9fTwTcsCtxgFuIKnTd7rjjqOGj2fnOQ4fhpezhpno4_4KPqcvYyiALtt7DD5RGgkyK0-jg6Kipke0TtjLBz77AXKO9cLRu6HNMS4eGR0vEWs1ZXo_qrShWxfzdlM5VP99yCKIGi0X3Br0_1xKOojwMfBdmh77ieHANDNYxdqanW9ID4alzaeIJdq7iVrREyw2e9C2rM9CXxhuEJSRM5NL9grDztC8HdIQS6yhdu8gNngMq0qLZG9DMzmtyxP6MSzntYAMN3JbARH7Egqn3aCEf6NuQCQ Download .mp4 (0.49 MB) Help with .mp4 files Supplementary online movie 2eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJhNDNjZTdhZmVmNDcxMDFmMmVlMWI4OTljNDU1OWNjNCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjM0NTQ0MTU3fQ.mHB8em-qK5rJV8bq8G4UgOIohHHaQOLBFNjHf9DyyQ8IHs4QGBxec0eI6Rt685yicKS7uvqtPvrlKlN5HSEYj2aAamtZp-A3IBdBg1eIFS5QFqRcl08bY4tNAVKgSxmZRE3oXPk0lYBJmJfLCRMpz_OJAlqajtsY21m1QMS7tqCm1sCO9zZckO1UWKxYVaBpzufzuELNyPKR6RXkc3W4tkJa_zyjzGX4jYOxv0UMEkkS8a8e5qKt3fDZNsL00qXJSdM636bkE1JarZbKZD_aay_YMA_EwVwn_dpvE5fH9lnOnCKi-ldvdg_Oxy_98NtXyktBenbXAwwmtdlNa5yQOA Download .mp4 (0.82 MB) Help with .mp4 files Supplementary online movie 3 Histological findings determined by hematoxylin and eosin staining were classified using the Solez score.18.Solez K. Morel-Maroger L. Sraer J.D. The morphology of ‘acute tubular necrosis’ in man: analysis of 57 renal biopsies and a comparison with the glycerol model.Medicine (Baltimore). 1979; 58: 362-376Crossref PubMed Scopus (361) Google Scholar Kidneys undergoing 45 min of renal artery clamping and 7 days of reperfusion (I/R) thereby showed significant ischemia-induced damage particularly within the renal tubuli, compared with non-ischemic controls, including detachment of the tubulus epithelial cells (I/R: 1.40±0.10 versus control: 0.39±0.08; P<0.01), interstitial edema (I/R: 1.25±0.13 versus control: 0.37±0.07; P<0.01), and tubular cell casts (I/R: 2.25±0.24 versus control: 0.42±0.07; P<0.01) (Figure 3b and d) (Figure 3a and d). In contrast, renal histology obtained after BH4 supplementation revealed significantly diminished changes and reduced quantitative renal tissue damage scores (epithelial detachment: I/R 1.40±0.10 versus I/R+BH4: 0.45±0.06; P<0.01; interstitial edema: I/R: 1.25±0.13 versus I/R+BH4: 0.51±0.08; P<0.01; tubular cell cast: I/R: 2.25±0.24 versus I/R+BH4: 1.33±0.11; P<0.01) (Figure 3c and d). The nitrosylation of tyrosine is paradigmatic for the reaction of peroxynitrite (ONOO-) with aromatic amino acids and is therefore an indirect marker for this strong oxidative agent. Immunostaining for nitrotyrosine was thus performed to indirectly estimate peroxynitrite generation (Figure 4). Compared with non-ischemic controls (Figure 4a), peroxynitrite formation and hence nitrotyrosine staining were significantly increased following 45 min of warm ischemia (Figure 4b), which could be abrogated almost entirely by BH4 treatment (Figure 4c). For quantification purposes, the product of the proportion of positive cells and the staining intensity was calculated, yielding a total immunostaining score ranging from 0 to 12 (Figure 4d). Immunostaining was significantly higher in untreated kidneys (I/R: 7.56±0.45) compared with BH4-treated kidneys (I/R+BH4: 2.22±0.45) or non-ischemic controls (control: 0.85±0.54). In addition, intragraft peroxynitrite generation correlated significantly with the impairment of renal microcirculation and FCD scores. (Spearman: r=-0.58; P<0.01; data from Figure 4d). A similar staining pattern was also observed at 2 h following reperfusion (I/R: 5.53±0.88; I/R+BH4: 1.65±0.58; control: 1.08±0.49), whereas histomorphology only revealed moderate tissue edema but no other morphologic changes such as tubular cell cast or detachment of tubulus epithelial cells at such an early time point following ischemic injury (data not shown). Renal function was assessed using serum creatinine and urea as indirect parameters of glomerular function. Both parameters were significantly increased after renal ischemia in untreated animals (I/R) after 24 h (Cr: 2.14±0.81 mg/dl; U: 286.67±55.28 mg/dl) and 48 h (Cr: 1.34±0.24 mg/dl; U: 196.02±40.00 mg/dl) following reperfusion compared with non-ischemic sham-operated controls (sham) Cr: 0.65±0.18 mg/dl; U: 82.58±14.25 mg/dl at 24 h and Cr: 0.44±0.24 mg/dl; U: 68.27±21.94 mg/dl at 48 h. The administration of a single dose of BH4 (I/R+BH4) before ischemia resulted in significantly improved renal function and reduced serum creatinine and urea levels Cr: 0.58±0.19 mg/dl; U: 84.10±20.70 mg/dl at 24 h and Cr: 0.48±0.13 mg/dl; U: 81.77±22.48 mg/dl at 48 h after reperfusion (Figure 5a and b). In line with animals subjected to ischemic injury, only rats undergoing life-supporting kidney transplantation following bilateral nephrectomy (TX) also showed significant increases in serum creatinine and urea after 24 h (Cr: 2.41±0.43 mg/dl; U: 292.0±51.40 mg/dl), 48 h (Cr: 3.75±1.20 mg/dl; U: 452.40±202.5 mg/dl), and 7 days (Cr: 1.40±0.13 mg/dl; U: 210.50±226.3 mg/dl) after transplantation without treatment. The administration of a single dose of BH4 (20 mg/kg per body weight) to the donor and recipient before organ recovery and revascularization (TX+BH4), respectively, resulted in significantly improved renal function at 24 h (Cr: 1.53±0.92 mg/dl; U: 266.50±71.55 mg/dl), 48 h (Cr: 1.65±0.73 mg/dl; U: 341.50±230.20 mg/dl), and 7 days (Cr: 0.56±0.20; U: 119.60±44.89 mg/dl) after transplantation. In addition to improved graft function, BH4 therapy also increased animal survival rates from 33.2% in the untreated control group (TX) to 66.7% in the BH4-treated group (TX+BH4) (P<0.01). In this study, we were able to show that BH4 supplementation significantly protects kidneys from IRI. Moreover, BH4 restores ischemia-induced microcirculatory disorders, diminishes histological damage such as epithelial detachment, tubular cell cast, and interstitial edema, and abrogates peroxynitrite formation consequently resulting in improved renal function. It has been previously shown that BH4, a cofactor of all NOS isoforms, is one of the most powerful naturally occurring reducing substances having direct antioxidant effects contributing to its cytoprotective action.19.Kojima S. Ona S. Iizuka I. et al.Antioxidative activity of 5,6,7,8-tetrahydrobiopterin and its inhibitory effect on paraquat-induced cell toxicity in cultured rat hepatocytes.Free Radic Res. 1995; 23: 419-430Crossref PubMed Scopus (85) Google Scholar Several studies have suggested that the availability of BH4 is essential for the formation and stabilization of NOS. The absence of BH4 results in an uncoupling of the NOS enzyme and subsequently causes superoxide formation instead of NO, thereby contributing substantially to oxidative injury following ischemia reperfusion.20.Cosentino F. Luscher T.F. Tetrahydrobiopterin and endothelial nitric oxide synthase activity.Cardiovasc Res. 1999; 43: 274-278Crossref PubMed Scopus (144) Google Scholar The loss of BH4 is likely the result of oxidative degradation secondary to the formation of oxidants and oxygen-free radicals that are enhanced during kidney ischemia and reperfusion. In particular, the endothelium is considered to generate free radicals during IRI. Furthermore, oxyradical injury alters the redox state of endothelial cells and thus impairs BH4 availability, as the biosynthesis of BH4 depends on a normal cellular redox state.21.Kim M.K. Sasaki S. Sasazuki S. et al.Lack of long-term effect of vitamin C supplementation on blood pressure.Hypertension. 2002; 40: 797-803Crossref PubMed Scopus (96) Google Scholar In this study, BH4 concentrations were found to be significantly decreased following 45 min of warm ischemia compared with non-ischemic controls; however, this could be reversed sufficiently by a single dose of exogenous BH4 delivery. We therefore hypothesized that: (i) BH4 depletion in post-ischemic kidneys may lead to the uncoupling of NOS, increased peroxynitrite (ONOO-) formation, and loss of microcirculatory integrity resulting in impaired renal function and (ii) that BH4 supplementation would be effective in restoring these alterations. To examine precisely the role of BH4 in post-ischemic kidney microcirculation, studies were performed in a rat kidney ischemia–reperfusion model using the renal pedicle clamp approach. Clinical effects in terms of improved renal function were additionally assessed in a rat kidney transplant model. One of the hallmarks of ARF and delayed graft function are ischemia–reperfusion-related disturbances in microcirculation with subsequent endothelial dysfunction, enhanced leukocyte–endothelial interaction, and hypoxic tissue damage.22.Sutton T.A. Kelly K.J. Mang H.E. et al.Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury.Am J Physiol Renal Physiol. 2005; 288: F91-F97Crossref PubMed Scopus (111) Google Scholar,23.Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar Certainly, endothelial injury and peritubular capillary dysfunction may initiate and extend the pathogenesis of ARF, and also contribute to ischemic forms of ARF by compromising renal vascular responsiveness and tubule function.24.Wu L. Mayeux P.R. Effects of the inducible nitric-oxide synthase inhibitor L-N(6)-(1-iminoethyl)-lysine on microcirculation and reactive nitrogen species generation in the kidney following lipopolysaccharide administration in mice.J Pharmacol Exp Ther. 2007; 320: 1061-1067Crossref PubMed Scopus (44) Google Scholar In addition, localized alterations in kidney blood flow persist after ischemic injury and have a major role in the extension of ischemic injury following reperfusion. Congestion in renal microcirculation, especially in the capillaries of the outer medullary vasa recta, contributes to deficits in oxygen and substrate delivery.3.Sharfuddin A.A. Sandoval R.M. Berg D.T. et al.Soluble thrombomodulin protects ischemic kidneys.J Am Soc Nephrol. 2009; 20: 524-534Crossref PubMed Scopus (97) Google Scholar,25.Sharfuddin A.A. Sandoval R.M. Molitoris B.A. Imaging techniques in acute kidney injury.Nephron Clin Pract. 2008; 109: c198-c204Crossref PubMed Scopus (15) Google Scholar As microcirculatory dysfunction is a common feature of various forms of renal injury, IVM has become the preferred and unique mode of documenting and directly monitoring changes in peritubular capillary flow following renal ischemia.26.Yamamoto T. Tada T. Brodsky S.V. et al.Intravital videomicroscopy of peritubular capillaries in renal ischemia.Am J Physiol Renal Physiol. 2002; 282: F1150-F1155Crossref PubMed Scopus (152) Google Scholar Microcirculation as assessed by IVM in our study was significantly impaired in post-ischemic kidneys reflected by persistently reduced FCD and CD. This impairment might occur secondary to a loss of NO production from NOS with a shift of the enzyme toward the generation of O2- instead of NO. This shift may be triggered by the observed near-total depletion of BH4 during ischemia.27.Maglione M. Hermann M. Hengster P. et al.Tetrahydrobiopterin attenuates microvascular reperfusion injury following murine pancreas transplantation.Am J Transplant. 2006; 6: 1551-1559Crossref PubMed Scopus (13) Google Scholar Exogenous BH4 treatment probably restores NO production from NOS and therefore enhanced the post-ischemic recovery of kidneys. Thus, it is reasonable to speculate that BH4 levels are a key factor modulating NOS activity, NO production, peroxynitrite generation, and microcirculation in post-ischemic kidneys. Indeed, in this study, BH4 supplementation not only attenuated microcirculatory damage but also significantly decreased peroxynitrite formation, as reflected by diminished nitrotyrosine staining scores. Peroxynitrite is generated by the rapid interaction of superoxide anions with NO and has been associated with various deleterious effects on both cellular and tissue function including increased oxidative reactions, lipid peroxidation, and reduction of plasma antioxidants.28.Szabo C. DNA strand breakage and activation of poly-ADP ribosyltransferase: a cytotoxic pathway triggered by peroxynitrite.Free Radic Biol Med. 1996; 21: 855-869Crossref PubMed Scopus (209) Google Scholar,29.Beckman J.S. Koppenol W.H. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.Am J Physiol. 1996; 271: C1424-C1437PubMed Google Scholar Nitration of protein tyrosine residues leads to the formation of 3-nitrotyrosine, and thus may be considered as an indirect marker of peroxynitrite-dependent oxidative damage.30.Haddad I.Y. Pataki G. Hu P. et al.Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury.J Clin Invest. 1994; 94: 2407-2413Crossref PubMed Scopus (558) Google Scholar The generation of oxygen-free radicals is increased during reperfusion, depending on the severity and duration of the preceding ischemic period, and subsequently might also increase peroxynitrite formation.31.Bolli R. Jeroudi M.O. Patel B.S. et al.Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog.Proc Natl Acad Sci USA. 1989; 86: 4695-4699Crossref PubMed Scopus (428) Google Scholar This is in accord with recent data showing that reduced peritubular capillary perfusion may contribute to the generation of tubular epithelial oxidant generation. Wu and Mayeux24.Wu L. Mayeux P.R. Effects of the inducible nitric-oxide synthase inhibitor L-N(6)-(1-iminoethyl)-lysine on microcirculation and reactive nitrogen species generation in the kidney following lipopolysaccharide administration in mice.J Pharmacol Exp Ther. 2007; 320: 1061-1067Crossref PubMed Scopus (44) Google Scholar showed that both reactive oxygen species32.Delles C. Schluter C. Wittmann M. et al.‘Very delayed’ graft function in a patient after living related kidney transplantation: a case report.Transplant Proc. 2004; 36: 1377-1379Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar and reactive nitrogen species were significantly increased in the tubular epithelium following a decrease in capillary perfusion resulting in a microenvironment that promotes oxidant generation and tubular injury. Also in line with this suggestion, 45 min of warm ischemia in this study revealed a significant increase in peroxynitrite formation and hence nitrotyrosine staining compared with non-ischemic controls, which significantly correlated with microcirculatory defects. Thus, our results showing decreased nitrotyrosine immunostaining owing to BH4 supplementation indicate that BH4 prevents the tyrosine-nitrating properties of peroxynitrite following IRI, leading to overall reduced injury. Therefore, BH4 may be considered to be protective against manifestations of oxidative and nitrosative stress in this experimental model of renal IRI. In this regard, apart from the protective effects on microcirculation and peroxynitrite formation, BH4 supplementation also significantly attenuated histopathologic tubular cell damage and improved kidney function as reflected by attenuated creatinine and urea levels during the early period after ischemia and reperfusion. Our data are also in line with previous findings by Kakoki et al.33.Kakoki M. Hirata Y. Hayakawa H. et al.Effects of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure.J Am Soc Nephrol. 2000; 11: 301-309PubMed Google Scholar who were the first to show, using a similar model of ischemic ARF and treatment regimen, that a single oral dose of BH4 administered before ischemia markedly improved acetylcholine-induced vasorelaxation and NO release in the isolated perfused kidney. In addition, exogenous supplementation of BH4 in their study restored calcium-dependent NO" @default.
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