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1.
Kidney Int ; 74(1): 47-51, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18368029

ABSTRACT

Vascular access dysfunction contributes to patient morbidity during maintenance hemodialysis. In this study we determined if knockout of heme oxygenase-1 predisposed to malfunction of arteriovenous fistulas. After three weeks, all fistulas in wild type mice were patent whereas a third of the fistulas in knockout mice were occluded and these exhibited increased neointimal hyperplasia and venous wall thickening. Heme oxygenase-1 mRNA and protein were robustly induced in the fistulas of the wild type mice. In the knockout mice there was increased PAI-1 and MCP-1 expression, marked induction of MMP-2 and MMP-9, but similar expression of PDGF alpha, IGF-1, TGF-beta1, VEGF, and osteopontin compared to wild type mice. We conclude that heme oxygenase-1 deficiency promotes vasculopathic gene expression, accelerates neointimal hyperplasia and impairs the function of arteriovenous fistulas.


Subject(s)
Catheters, Indwelling/adverse effects , Heme Oxygenase-1/deficiency , Animals , Arteriovenous Shunt, Surgical , Blood Vessels/injuries , Blood Vessels/pathology , Gene Expression Profiling , Gene Expression Regulation , Heme Oxygenase-1/genetics , Heme Oxygenase-1/physiology , Mice , Mice, Knockout , Tunica Intima/pathology
2.
Kidney Int ; 72(9): 1073-80, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17728706

ABSTRACT

Heme oxygenase-1 may exert cytoprotective effects. In this study we examined the sensitivity of heme oxygenase-1 knockout (HO-1(-/-)) mice to renal ischemia by assessing glomerular filtration rate (GFR) and cytokine expression in the kidney, and inflammatory responses in the systemic circulation and in vital extrarenal organs. Four hours after renal ischemia, the GFR of HO-1(-/-) mice was much lower than that of wild-type mice in the absence of changes in renal blood flow or cardiac output. Eight hours after renal ischemia, there was a marked induction of interleukin-6 (IL-6) mRNA and its downstream signaling effector, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), in the kidney, lung, and heart in HO-1(-/-) mice. Systemic levels of IL-6 were markedly and uniquely increased in HO-1(-/-) mice after ischemia as compared to wild-type mice. The administration of an antibody to IL-6 protected against the renal dysfunction and mortality observed in HO-1(-/-) mice following ischemia. We suggest that the exaggerated production of IL-6, occurring regionally and systemically following localized renal ischemia, in an HO-1-deficient state may underlie the heightened sensitivity observed in this setting.


Subject(s)
Glomerular Filtration Rate/physiology , Heme Oxygenase-1/metabolism , Ischemia/physiopathology , Kidney/blood supply , Animals , Cardiac Output/physiology , Cytokines/blood , Female , Heme Oxygenase-1/genetics , Interleukin-6/metabolism , Ischemia/metabolism , Kidney/metabolism , Kidney/physiopathology , Lung/metabolism , Male , Mice , Mice, Knockout , Myocardium/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Regional Blood Flow/physiology , Reperfusion Injury/metabolism , Reperfusion Injury/physiopathology , STAT3 Transcription Factor/metabolism , Time Factors
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