The role of nitric oxide in renal transplantation

Vos, I.H.C.; Joles, Jaap A.; Rabelink, Ton J.

doi:10.1016/j.semnephrol.2004.04.009

Cited by 20 publications

(21 citation statements)

References 84 publications

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“…Our theoretical analyses reveal that ARG1 and NOS2A are also connected with another putative interaction leader, that is, RAC1 [Kuncewicz et al, 2001]. Endothelial integrity, especially the expression of protecting vasoactive agents, such as NO, may be a key factor in resistance or sensitivity to transplantation-mediated injury [Vos et al, 2004]. Taken together, these experimental and theoretical findings support the involvement of WNT pathway and NO synthesis into kidney transplant tolerance.…”

Section: Discussionsupporting

confidence: 61%

AKT1 leader gene and downstream targets are involved in a rat model of kidney allograft tolerance

Jovanović

Giacomelli

Sivozhelezov

et al. 2010

J of Cellular Biochemistry

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Tolerance is the so-called "Holy Grail" of transplantation but achieving this state is proving a major challenge, particularly in the clinical settings. This tolerance state can be induced in rodent models using a variety of maneuvers. This phenomenon is classically characterized by donor specificity (recipients accept a secondary donor-specific allograft but reject third-party allograft) as well as by the absence of chronic rejection lesion. We previously showed that administration and anti-donor anti-class II serum on the day of transplantation induce tolerance to a kidney allograft in the LEW-1W to LEW-1A strain combination. In this study, we used DNA microarrays to compare gene patterns involved in anti-donor anti-class II tolerated or untreated syngeneic kidney transplants in this strain combination. Statistical and non-statistical analyses were combined with ab initio analysis, using the recently developed leader gene approach, to shed new light on this phenomenon. Theoretical and experimental results suggest that tolerance and rejection outcome may be in large part determined by low expression variations of some genes, which can form a core gene network around specific genes such as Rac1, NFKB1, RelA, AKT1, IKBKB, BCL2, BCLX, and CHUK. Through this model, we showed that AKT1 gene, WNT pathway and NO synthesis are strictly connected to each other and may play an important role in kidney tolerance and rejection processes, with AKT1 gene being the center of this complex network of interactions.

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Section: Discussionsupporting

confidence: 61%

AKT1 leader gene and downstream targets are involved in a rat model of kidney allograft tolerance

Jovanović

Giacomelli

Sivozhelezov

et al. 2010

J of Cellular Biochemistry

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“…45 Our data suggest that the beneficial effects of FTY720 on kidney graft rejection for which it is currently undergoing Phase III clinical trials 1 may depend not only on its immunosuppressive function but also on its vasoactive, NO-generating potential in the endothelium we have characterized in our study. Accordingly, optimal efficacy of FTY720 in models of transplantation required at least 5-fold higher concentrations than those needed for maximal lymphocyte trapping in lymphoid organs.…”

Section: Discussionmentioning

confidence: 64%

Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P ₃

Tölle

Levkau

Keul

et al. 2005

Circulation Research

115

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Abstract-The novel immunomodulator FTY720 is effective in experimental models of transplantation and autoimmunity, and is currently undergoing Phase III clinical trials for prevention of kidney graft rejection. FTY720 is a structural analogue of sphingosine-1-phosphate (S1P) and activates several of the S1P receptors. We show that FTY720 induces endothelium-dependent arterial vasodilation in phenylephrine precontracted mouse aortae. Vasodilation did not occur in thoracic aortic rings from eNOS-deficient mice, implicating and effect dependent of activation of the eNOS/NO pathway. Accordingly, FTY720 induced NO release, Akt-dependent eNOS phosphorylation and activation in human endothelial cells. For biological efficacy, FTY720 required endogenous phosphorylation, since addition of the sphingosine kinase antagonist NЈ,N-dimethylsphingosine (DMS) prevented activation of eNOS in vitro and inhibited vasodilation in isolated arteries. The endothelial phosphorylation of FTY720 was extremely rapid with almost complete conversion after 10 minutes as determined by mass spectrometry. Finally, we identified the lysophospholipid receptor S1P 3 as the S1P receptor responsible for arterial vasodilation by FTY720, as the effect was completely abolished in arteries from S1P 3 -deficient mice. In summary, we have identified FTY720 as the first immunomodulator for prevention of organ graft rejection in clinical development that, in addition, positively affects the endothelium by stimulating NO production, and thus potentially displaying beneficial effects on transplant survival beyond classical T cell immunosuppression. Key Words: FTY720 Ⅲ eNOS Ⅲ S1P receptor T he novel immunomodulator FTY720 is currently undergoing Phase III clinical trials for prevention of kidney graft rejection. 1 FTY720 shares striking structural homology to sphingosine 1-phosphate (S1P), 2 a natural lysophospholipid that is present at high nanomolar (nmol/L) concentrations in serum. 3 Recent data show that FTY720 is phosphorylated in vivo by sphingosine-kinase-2 (SphK2), 4 and that the FTY720-phosphate metabolite (FTY720-P) is a potent agonist of 4 of the 5 G protein-coupled receptors for S1P: S1P 1 , S1P 3 , S1P 4 , and S1P 5 . 2,5 Recent studies show that the S1P 1 receptor and its natural ligand S1P are pivotal to lymphocyte recirculation: mice with a specific deletion of S1P 1 in hematopoietic cells showed that thymocytes selectively require S1P 1 for egress from thymus, whereas both T and B cells require this receptor for egress from peripheral lymphoid organs. 6 Thus, it was suggested that the efficacy of FTY720 in transplantation and autoimmunity may relate primarily to an inhibition of effector T cell recirculation from lymphoid organs to peripheral sites of inflammation. S1P receptor agonists mediate a variety of physiological processes and stimulate multiple signaling pathways resulting in calcium mobilization from intracellular stores, polymerization of actin, chemotaxis/migration, and escape from apoptosis. 7-10 S1P is released by platelets durin...

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“…It is therefore possible that intrarenal oxygenation is involved in the generation of reactive oxygen/ nitrogen species (ROS/RNS) and that, conversely, increased ROS/RNS result in tubular injury and decreased oxygen extraction/consumption in CAN. Various stimuli, e.g., CNIs (7,14), inflammation (31,52,74), hypoalbuminemia (31), and acidic urine (47), could have contributed to the generation of ROS/RNS (4,10,18,19,68) (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction

Djamali¹,

Sadowski²,

Muehrer³

et al. 2007

American Journal of Physiology-Renal Physiology

111

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Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) uses deoxyhemoglobin as an endogenous contrast agent for the noninvasive assessment of tissue oxygen bioavailability. We hypothesized that intrarenal oxygenation was impaired in patients with chronic allograft nephropathy (CAN). Ten kidney-transplant recipients with CAN and nine healthy volunteers underwent BOLD-MRI. Medullary R2* (MR2*) and cortical R2* (CR2*) levels (measures directly proportional to tissue deoxyhemoglobin levels) were determined alongside urine and serum markers of oxidative stress (OS): hydrogen peroxide (H(2)O(2)), F(2)-isoprostanes, total nitric oxide (NO), heat shock protein 27 (HSP27), and total antioxidant property (TAOP). Mean MR2* and CR2* levels were significantly decreased in CAN (increased local oxyhemoglobin concentration) compared with healthy volunteers (20.7 +/- 1.6 vs. 23.1 +/- 1.8/s, P = 0.03 and 15.9 +/- 1.9 vs. 13.6 +/- 2.3/s, P = 0.05, respectively). There was a significant increase in serum and urine levels of H(2)O(2) and serum HSP27 levels in patients with CAN. Conversely, urine NO levels and TAOP were significantly increased in healthy volunteers. Multiple linear regression analyses showed a significant association between MR2* and CR2* levels and serum/urine biomarkers of OS. BOLD-MRI demonstrated significant changes in medullary and cortical oxygen bioavailability in allografts with CAN. These correlated with serum/urine biomarkers of OS, suggesting an association between intrarenal oxygenation and OS.

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The role of nitric oxide in renal transplantation

Cited by 20 publications

References 84 publications

AKT1 leader gene and downstream targets are involved in a rat model of kidney allograft tolerance

AKT1 leader gene and downstream targets are involved in a rat model of kidney allograft tolerance

Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P ₃

BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction

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The role of nitric oxide in renal transplantation

Cited by 20 publications

References 84 publications

AKT1 leader gene and downstream targets are involved in a rat model of kidney allograft tolerance

AKT1 leader gene and downstream targets are involved in a rat model of kidney allograft tolerance

Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P 3

BOLD-MRI assessment of intrarenal oxygenation and oxidative stress in patients with chronic kidney allograft dysfunction

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Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P ₃