Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Huber, JM; Tagwerker, A; Heininger, D; Mayer, G; Rosenkranz, AR; Eller, K.
The proteasome inhibitor bortezomib aggravates renal ischemia-reperfusion injury.
Am J Physiol Renal Physiol. 2009; 297(2):F451-F460
Doi: 10.1152/ajprenal.90576.2008
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- Führende Autor*innen der Med Uni Graz
- Eller Kathrin
- Co-Autor*innen der Med Uni Graz
- Rosenkranz Alexander
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- Abstract:
- Bortezomib is a well-established treatment option for patients with multiple myeloma (MM). It is a selective and reversible inhibitor of the proteasome that is responsible for the degradation of many regulatory proteins that are involved in apoptosis, cell-cycle regulation, or transcription. Because patients with MM are prone to develop acute renal failure, we evaluated the influence of bortezomib on renal ischemia-reperfusion injury (IRI). Mice were subjected to renal IRI by having the renal pedicles clamped for 30 min followed by reperfusion for 3, 24, and 48 h. Mice were either pretreated with 0.5 mg/kg body wt bortezomib or vehicle intravenously 12 h before induction of IRI. Serum creatinine and tubular necrosis were significantly increased in bortezomib compared with vehicle-treated mice. The inflammatory response was found to be significantly decreased in bortezomib-treated mice as reflected by a decreased infiltration of CD4(+) T cells and a significantly decreased Th1 cytokine expression in the kidneys. In contrast, apoptosis was significantly increased in kidneys of bortezomib-treated mice compared with vehicle-treated controls. Increased numbers of TUNEL-positive cells/mm(2) and increased mRNA expression of proapoptotic factors were detected in kidneys of bortezomib-treated mice. Of note, p21, a cell senescence marker, was also significantly increased in kidneys of bortezomib-treated mice. In summary, we provide evidence that bortezomib worsens the outcome of renal IRI by leading to increased apoptosis of tubular cells despite decreased infiltrating T cells and proinflammatory mediators.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Anti-Inflammatory Agents - toxicity
- Apoptosis - drug effects
- Boronic Acids - administration and dosage Boronic Acids - toxicity
- CD4 Lymphocyte Count -
- Creatinine - blood
- Cyclin-Dependent Kinase Inhibitor p21 - metabolism
- Cytokines - metabolism
- Disease Models, Animal -
- Dose-Response Relationship, Drug -
- Injections, Intravenous -
- Kidney - drug effects Kidney - enzymology Kidney - immunology Kidney - pathology
- Kidney Diseases - chemically induced Kidney Diseases - enzymology Kidney Diseases - immunology Kidney Diseases - pathology
- Male -
- Mice -
- Mice, Inbred C57BL -
- Necrosis -
- Nephritis - enzymology Nephritis - immunology Nephritis - prevention and control
- Protease Inhibitors - administration and dosage Protease Inhibitors - toxicity
- Proteasome Endopeptidase Complex - antagonists and inhibitors Proteasome Endopeptidase Complex - metabolism
- Pyrazines - administration and dosage Pyrazines - toxicity
- Reperfusion Injury - chemically induced Reperfusion Injury - enzymology Reperfusion Injury - immunology Reperfusion Injury - pathology
- Time Factors -
- Find related publications in this database (Keywords)
- inflammation
- T cells
- apoptosis
- senescence