Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokines play a prominent role in the acute inflammatory response in several models of kidney disease. We reported that monocyte chemotactic peptide-1 (MCP-1) mRNA is increased by ischemia-reperfusion injury. In this report, we examined the effects of ischemia-reperfusion injury on the kinetics and location of MCP-1 protein expression, the excretion of MCP- 1 protein in the urine and on the infiltration of mononuclear cells in the kidney. Pair-fed Sprague-Dawley rats underwent bilateral renal ischemia (50 min) or sham ischemia and placed in metabolic cages for daily urine collections. Kidneys were harvested at d. 1, 3, 7, and 10 after ischemia-reperfusion (I-R) or sham-ischemia (S-I). Kidney MCP-1 mRNA levels were increased on d. I and 3 post-ischemia. Kidney MCP-1 protein levels were increased in the I-R group on d. 1 and 3. MCP-1 expression occurred predominantly in the distal tubule segments by immunohistology. There was an increase in monocytes/macrophages infiltration in the I-R group, compared to the S-I or controls by d. 1. Urinary MCP-1 excretion increased 3-fold in the I-R group, and remained elevated above the S-I group and baseline levels, on d. 3 through d. 8. Kidney MCP-1 mRNA levels, protein levels and urinary MCP-1 excretion rates are increased by ischemia-reperfusion injury. The areas of increase in MCP-1 chemoattractant expression correlates with an increase in monocyte infiltration in the kidney. Although its pathophysiologic role remains to be determined, MCP-1 may participate in, and be a biomarker for, the mononuclear inflammatory processes that occur after ischemia-induced acute renal failure.
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PMID:Monocyte chemoattractant protein-1 expression correlates with monocyte infiltration in the post-ischemic kidney. 1247 94

A long-lasting renal ischemia, followed by the left renal artery clipping (two-kidney, one clip Goldblatt model in rats) led to a marked decrease in proteasome chymotrypsin-like activity in the ischemic kidney. This activity was, however, significantly raised upon the stimulation with an artificial 20S proteasome activator SDS (0.025%). No changes were observed in either the levels of the constitutive 20S proteasome subunit (alpha5) or of its protein activator, PA28alpha, in the kidneys by Western blot. These preliminary results indicate that an inhibition of proteasome activity may result from a dissociation of the active proteasome complexes into the inactive 20S proteasome and its endogenous activators after a long-lasting renal ischemia.
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PMID:Changes in proteasome activity in the ischemic kidney of rat with experimental renovascular hypertension. 1563 41

Immuno-proteasome is thought to be responsible for the processing of intracellular antigens and is induced when cells are treated with the inflammatory cytokines promoting cellular immunity. We tested the possibility that immuno-proteasome can be up-regulated in renal cells exposed to a long-lasting ischemia and inflammation in an experimental model of two-kidney, one-clip renovascular hypertension in the rat. Western blotting showed that immuno-proteasome subunit, LMP7, was up-regulated in the clipped ischemic kidney that was atrophic, but not in the contralateral unclipped kidney that underwent compensatory hypertrophy. Immunohistochemical analysis revealed that LMP7 was highly expressed in cortical epithelial and endothelial cells of the ischemic kidney. Surprisingly, the second immuno-subunit, LMP2, was almost undetectable, indicating that renal ischemia may induce exclusively the LMP7 subunit. We also found that renal ischemia neither reduced the SDS-stimulated proteasomal activity nor affected a high level of the PA28 activator. Thus, the results provide evidence that LMP7 immuno-subunit is induced in renal cells exposed to a long-lasting renal ischemia and inflammation, and that there is a direct link between LMP induction and renal atrophy. This opens an opportunity to study a role for LMP-containing proteasomes in the kidneys and other organs undergoing reduction in mass in diseases accompanied by a long-lasting ischemia and inflammatory responses.
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PMID:Immuno-proteasome subunit LMP7 is up-regulated in the ischemic kidney in an experimental model of renovascular hypertension. 1676 38

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.
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PMID:The proteasome inhibitor bortezomib aggravates renal ischemia-reperfusion injury. 1945 22