renal-ischaemia-reperfusion-injury-mouse-model-injury

Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration

Renal ischaemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) in patients and occlusion of renal blood flow is unavoidable ...

mouse-kidney-transplantation-models-of-allograft-rejection

Mouse Kidney Transplantation: Models of Allograft Rejection

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely ...

a-murine-model-irreversible-reversible-unilateral-ureteric

A Murine Model of Irreversible and Reversible Unilateral Ureteric Obstruction

Obstruction of the kidney may affect native or transplanted kidneys and results in kidney injury and scarring. Presented here is a model of obstructive ...

University of Edinburgh

The University of Edinburgh

Ischemic preconditioning (IPC) protects organs from ischemia reperfusion injury (IRI) through unknown mechanisms. Effector T cell populations have been implicated in the pathogenesis of IRI, and T regulatory cells (Treg) have become a putative therapeutic target, with suggested involvement in IPC. We explored the role of Treg in hepatic IRI and IPC in detail. IPC significantly reduced injury following ischemia reperfusion insults. Treg were mobilized rapidly to the circulation and liver after IRI, but IPC did not further increase Treg numbers, nor was it associated with modulation of circulating pro-inflammatory chemokine or cytokine profiles. We used two techniques to deplete Treg from mice prior to IRI. Neither Treg depleted FoxP3.LuciDTR mice, nor wildtyoe mice depleted of Tregs with PC61, were more susceptible to IRI compared with controls. Despite successful enrichment of Treg in the liver, by adoptive transfer of both iTreg and nTreg or by in vivo expansion of Treg with IL-2/anti-IL-2 complexes, no protection against IRI was observed.We have explored the role of Treg in IRI and IPC using a variety of techniques to deplete and enrich them within both the liver and systemically. This work represents an important negative finding that Treg are not implicated in IPC and are unlikely to have translational potential in hepatic IRI.

Ischemic preconditioning in the liver is independent of regulatory T cell activity.

Pr&eacute;conditionnement isch&eacute;mique (IPC) prot&egrave;ge les organes de la l&eacute;sion de reperfusion de l&#39;isch&eacute;mie (IRI) par le biais de m&eacute;canismes inconnus. Les populations de lymphocytes T effecteurs sont impliqu&eacute;es dans la pathogen&egrave;se de l&#39;IRI, et les lymphocytes T r&eacute;gulateurs (Treg) sont devenus une cible th&eacute;rapeutique putative, avec participation sugg&eacute;r&eacute;e dans la CIB. Nous avons explor&eacute; le r&ocirc;le de Treg dans IRI h&eacute;patique et IPC en d&eacute;tail. CIB a consid&eacute;rablement r&eacute;duit apr&egrave;s les insultes de l&#39;isch&eacute;mie reperfusion des blessures. Treg se sont mobilis&eacute;s rapidement &agrave; la circulation et foie apr&egrave;s que IRI, mais IPC ne pas plus loin augmenter le nombre de Treg, ni il &eacute;tait associ&eacute;e &agrave; la modulation des profils de chemokine ou de cytokines pro-inflammatoires en circulation. Nous avons utilis&eacute; deux techniques pour appauvrir Treg des souris avant IRI. Ni Treg appauvri souris FoxP3.LuciDTR, ni wildtyoe souris appauvris en Tregs avec PC61, ont &eacute;t&eacute; plus sensibles &agrave; l&#39;IRI, comparativement aux t&eacute;moins. Malgr&eacute; l&#39;enrichissement r&eacute;ussie de Treg dans le foie, par transfert adoptif d&#39;iTreg et nTreg ou expansion in vivo de Treg avec des complexes d&#39;IL-2/anti-IL-2, aucune protection contre l&#39;IRI a &eacute;t&eacute; observ&eacute;e.Nous avons explor&eacute; le r&ocirc;le de Treg IRI et la CIB &agrave; l&#39;aide de diverses techniques d&#39;&eacute;puiser et de les enrichir dans les deux le foie et syst&eacute;mique. Ce travail repr&eacute;sente une d&eacute;couverte importante n&eacute;gative que Treg ne sont pas impliqu&eacute;s dans la CIB et ne risquent pas d&#39;avoir un potentiel translationnelle dans IRI h&eacute;patique.

Il est ind&eacute;pendant de l&#39;activit&eacute; des lymphocytes T r&eacute;gulateurs de pr&eacute;conditionnement isch&eacute;mique dans le foie.

Precondizionamento ischemico (IPC) protegge gli organi da danno di ischemia da riperfusione (IRI), attraverso meccanismi sconosciuti. Popolazioni di cellule T effettrici sono state implicate nella patogenesi dell&#39;IRI, e le cellule T regolatori (Treg) sono diventati un obiettivo terapeutico putativo, con coinvolgimento suggerito in IPC. Abbiamo esplorato il ruolo di Treg in IRI epatica e IPC in dettaglio. IPC ridotto significativamente le lesioni a seguito di insulti di reperfusion di ischemia. Treg furono mobilitate rapidamente la circolazione e fegato dopo l&#39;IRI, ma IPC non ha fatto ulteriori aumentare numeri Treg, n&eacute; &egrave; stata associata la modulazione dei profili delle chemochine o citochine pro-infiammatori in circolazione. Abbiamo utilizzato due tecniche per esaurire Treg da topi prima dell&#39;IRI. N&eacute; Treg impoverito topi FoxP3.LuciDTR, n&eacute; wildtyoe topi impoverito di Tregs con PC61, erano pi&ugrave; suscettibili all&#39;IRI rispetto ai controlli. Malgrado successo arricchimento di Treg nel fegato, mediante trasferimento adottivo di iTreg e di nTreg o di espansione in vivo di Treg con complessi del-2/anti-IL-2, nessuna protezione contro l&#39;IRI &egrave; stato osservato.Abbiamo esplorato il ruolo di Treg in IRI e IPC utilizzando una variet&agrave; di tecniche per esaurire e arricchirle dentro entrambi fegato e sistemica. Questo lavoro rappresenta un&#39;importante constatazione negativa che Treg non sono implicati in IPC e difficilmente hanno potenziale traslazionale in IRI epatica.

Precondizionamento ischemico nel fegato &egrave; indipendente dell&#39;attivit&agrave; di regolamentazione delle cellule T.

Amelioration of rodent type 2 diabetes by hemin has been linked to increased heme oxygenase (HO) activity, however alternative mechanisms have recently been proposed for its anti-diabetic effect. We sought to determine the anti-diabetic efficacy of heme arginate (HA), a clinically licensed preparation of heme, and whether its predominant mode of action is via increased HO activity. Intravenous administration of HA reduced hyperglycemia in diabetic (db/db) mice. Co-administration of the HO inhibitor stannous (IV) mesoporphyrin IX dichloride (SM) resulted unexpectedly in a further improvement in glycaemic control despite restoring HO activity to baseline levels. The anti-diabetic effects of HA±SM were associated with increased adiposity, increased serum adiponectin levels, reduced adipose tissue and islet inflammation and preservation of islet β-cell function. HO activity independent effects of HA on adipogenesis and β-cell inflammation were further confirmed in cell culture models using the 3T3-L1 pre-adipocyte and MIN6 β-cell lines, respectively. In conclusion, our work demonstrates that the heme component of HA ameliorates experimental type 2 diabetes by promoting metabolically favourable adipogenesis and preserving islet β-cell function, but this is not mediated via increased HO activity.

Gary Borthwick

MRC Centre for Inflammation Research

University of Edinburgh

Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration

Mouse Kidney Transplantation: Models of Allograft Rejection

A Murine Model of Irreversible and Reversible Unilateral Ureteric Obstruction

Gary Borthwick

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}MRC Centre for Inflammation Research

University of Edinburgh

Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration

Mouse Kidney Transplantation: Models of Allograft Rejection

A Murine Model of Irreversible and Reversible Unilateral Ureteric Obstruction

MRC Centre for Inflammation Research