Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1(KI/KI)) mouse model, in which the caspase cleavage site of PARP-1, DEVD(214), was mutated to render the protein resistant to caspases during apoptosis. While PARP-1(KI/KI) mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-kappaB to DNA, NF-kappaB-mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies.
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PMID:Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice. 1548 54

The role of poly(ADP-ribose) (PAR) glycohydrolase (PARG) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Poly(ADP-ribosyl)ation is rapidly stimulated in cells after DNA damage caused by the generation of reactive oxygen and nitrogen species during I/R. Continuous or excessive activation of poly(ADP-ribose) polymerase-1 produces extended chains of ADP-ribose on nuclear proteins and results in a substantial depletion of intracellular NAD(+) and subsequently, ATP, leading to cellular dysfunction and, ultimately, cell death. The key enzyme involved in polymer turnover is PARG, which possesses mainly exoglycosidase activity but can remove olig(ADP-ribose) fragments via endoglycosidic cleavage. Thus, the aim of this study was to investigate whether the absence of PARG(110) reduced the renal dysfunction, injury, and inflammation caused by I/R of the mouse kidney. Here, the renal dysfunction and injury caused by I/R (bilateral renal artery occlusion [30 min] followed by reperfusion [24 h]) in mice lacking PARG(110), the major nuclear isoform of PARG, was investigated. The following markers of renal dysfunction and injury were measured: Plasma urea, creatinine, aspartate aminotransferase, and histology. The following markers of inflammation were also measured: Myeloperoxidase activity, malondialdehyde levels, and plasma nitrite/nitrate. The degree of renal injury and dysfunction caused by I/R was significantly reduced in PARG(110)-deficient mice when compared with their wild-type littermates, and there were no differences in any of the biochemical parameters measured between sham-operated PARG(110)(-/-) mice and sham-operated wild-type littermates. Thus, it is proposed that endogenous PARG(110) plays a pivotal role in the pathophysiology of I/R injury of the kidney.
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PMID:Mice lacking the 110-kD isoform of poly(ADP-ribose) glycohydrolase are protected against renal ischemia/reperfusion injury. 1567 8

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.
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PMID:Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury. 2208 94