title: The proteasome inhibitor bortezomib aggravates renal ischemia-reperfusion injury.
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.
authors.affiliation: Clinical Division of Internal Medicine IV-Nephrology and Hypertension, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Huber
authors.forename: Andrea
authors.initials: A
authors.lastname: Tagwerker
authors.forename: Dorothea
authors.initials: D
authors.lastname: Heininger
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Rosenkranz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eller
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000633:toxicity*; D000069286:Bortezomib; D018791:CD4 Lymphocyte Count; D003404:Creatinine / Q000097:blood; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009393:Nephritis / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000633:toxicity*; D015427:Reperfusion Injury / Q000139:chemically induced* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D001897:Boronic Acids; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003404:Creatinine; D046988:Proteasome Endopeptidase Complex