Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model

Bernhardt, Wanja M.; Göttmann, Uwe; Doyon, F; Buchholz, Björn; Câmpean, Valentina; Schödel, Johannes; Reisenbuechler, Anke; Klaus, Stephen J.; Arend, Michael; Flippin, Lee A.; Willam, Carsten; Wiesener, Michael S.; Yard, Benito A.; Warnecke, Christina; Eckardt, Kai‐Uwe

doi:10.1073/pnas.0903978106

Cited by 132 publications

(103 citation statements)

References 46 publications

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“…[1][2][3][4]29,30 Despite the suggestive clinical data, it has been difficult to directly test the contribution of initial IR injury to allograft rejection in experimental studies. 23 Our results, in conjunction with several recent intervention studies, 20,31 strongly support the hypothesis that therapeutic targeting of nonalloimmune IR injury can efficiently contribute to minimizing subsequent alloimmune processes and renal rejection. This is the first study showing that B␤ protects from acute kidney injury.…”

Section: Discussionsupporting

confidence: 70%

Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

Sörensen

Rong

Susnik

et al. 2011

Journal of the American Society of Nephrology

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Renal ischemia-reperfusion contributes to reduced renal allograft survival. The peptide B␤ 15-42 , a breakdown product of fibrin, attenuates inflammation induced by ischemia-reperfusion in the heart by competitively blocking the binding of leukocytes to endothelial VE-cadherin, but whether it could improve outcomes in renal transplantation is unknown. Here, we tested the ability of B␤ to ameliorate the effects of renal ischemic injury during allogenic kidney transplantation in mice. In our renal transplantation model (C57BL/6 into BALB/c mice), treatment with B␤ 15-42 at the time of allograft reperfusion resulted in significantly improved survival of recipients during the 28-day follow-up (60% versus 10%). B␤ 15-42 treatment decreased leukocyte infiltration, expression of endothelial adhesion molecules, and proinflammatory cytokines. Treatment significantly attenuated allogenic T cell activation and reduced cellular rejection. Moreover, B␤ 15-42 significantly reduced tubular epithelial damage and apoptosis, which we reproduced in vitro. These data suggest that B␤ 15-42 may have therapeutic potential in transplant surgery by protecting grafts from ischemia-reperfusion injury.

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Section: Discussionsupporting

confidence: 70%

Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

Sörensen

Rong

Susnik

et al. 2011

Journal of the American Society of Nephrology

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“…Furthermore, in rats and mice subjected to warm ischemia and refl ow, PHD inhibitors and carbon monoxide pre-treatment (i.e., functional anemia) markedly attenuated kidney damage and dysfunction [32,40]. Donor pre-treatment with a PHD inhibitor also prevented graft injury and prolonged survival in an allogenic kidney transplant model in rats [41]. Finally, rats preconditioned by carbon monoxide, displayed reduced cisplatin renal toxicity, with attenuation of renal dysfunction and the extent of tubular apoptosis and necrosis [42].…”

Section: Acute Kidney Injurymentioning

confidence: 94%

Hypoxia-inducible Factors and the Prevention of Acute Organ Injury

Heyman¹,

Rosen²,

Rosenberger³

2011

Annual Update in Intensive Care and Emergency Medicine 2011

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“…Our Hif-p4h-2 gt/gt mouse data suggest that pharmacological HIF-P4H-2 inhibition could also be beneficial for the treatment of obesity and metabolic syndrome. We therefore administered FG-4497 to wild-type mice with a metabolic dysfunction, which stabilizes HIF-a in cultured cells and in vivo and increases erythropoiesis in animals with no apparent toxicity (3,16,17). The data demonstrate that FG-4497 administration phenocopied the beneficial effects of genetic HIF-P4H-2 deficiency on adipose tissues and metabolism.…”

mentioning

confidence: 97%

HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

et al. 2014

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Obesity is a major public health problem, predisposing subjects to metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Specific prolyl 4-hydroxylases (P4Hs) regulate the stability of the hypoxia-inducible factor (HIF), a potent governor of metabolism, with isoenzyme 2 being the main regulator. We investigated whether HIF-P4H-2 inhibition could be used to treat obesity and its consequences. Hif-p4h-2–deficient mice, whether fed normal chow or a high-fat diet, had less adipose tissue, smaller adipocytes, and less adipose tissue inflammation than their littermates. They also had improved glucose tolerance and insulin sensitivity. Furthermore, the mRNA levels of the HIF-1 targets glucose transporters, glycolytic enzymes, and pyruvate dehydrogenase kinase-1 were increased in their tissues, whereas acetyl-CoA concentration was decreased. The hepatic mRNA level of the HIF-2 target insulin receptor substrate-2 was higher, whereas that of two key enzymes of fatty acid synthesis was lower. Serum cholesterol levels and de novo lipid synthesis were decreased, and the mice were protected against hepatic steatosis. Oral administration of an HIF-P4H inhibitor, FG-4497, to wild-type mice with metabolic dysfunction phenocopied these beneficial effects. HIF-P4H-2 inhibition may be a novel therapy that not only protects against the development of obesity and its consequences but also reverses these conditions.

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Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model

Cited by 132 publications

References 46 publications

Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

Hypoxia-inducible Factors and the Prevention of Acute Organ Injury

HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

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