Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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

Increased generation of reactive oxygen species (ROS) and the subsequent DNA damage and excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1) have been implicated in the pathogenesis of ischemic injury. We previously demonstrated that pharmacological inhibition of PARP protects against ischemic renal injury (IRI) in rats (Martin DR, Lewington AJ, Hammerman MR, and Padanilam BJ. Am J Physiol Regul Integr Comp Physiol 279: R1834-R1840, 2000). To further define the role of PARP-1 in IRI, we tested whether genetic ablation of PARP-1 attenuates tissue injury after renal ischemia. Twenty-four hours after reperfusion following 37 min of bilateral renal pedicle occlusion, the effects of the injury on renal functions in PARP-/- and PARP+/+ mice were assessed by determining glomerular filtration rate (GFR) and the plasma levels of creatinine. The levels of plasma creatinine were decreased and GFR was augmented in PARP-/- mice. Morphological evaluation of the kidney tissues showed that the extent of damage due to the injury in PARP-/- mice was less compared with their wild-type counterparts. The levels of ROS and DNA damage were comparable in the injured kidneys of PARP+/+ and PARP-/- mice. PARP activity was induced in ischemic kidneys of PARP+/+ mice at 6-24 h postinjury. At 6, 12, and 24 h after injury, ATP levels in the PARP+/+ mice kidney declined to 28, 26, and 43%, respectively, whereas it was preserved close to normal levels in PARP-/- mice. The inflammatory cascade was attenuated in PARP-/- mice as evidenced by decreased neutrophil infiltration and attenuated expression of inflammatory molecules such as TNF-alpha, IL-1beta, and intercellular adhesion molecule-1. At 12 h postinjury, no apoptotic cell death was observed in PARP-/- mice kidneys. However, by 24 h postinjury, a comparable number of cells underwent apoptosis in both PARP-/- and PARP+/+ mice kidneys. Thus activation of PARP post-IRI contributes to cell death most likely by ATP depletion and augmentation of the inflammatory cascade in the mouse model. PARP ablation preserved ATP levels, renal functions, and attenuated inflammatory response in the setting of IRI in the mouse model. PARP inhibition may have clinical efficacy in preventing the progression of acute renal failure complications.
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PMID:Poly(ADP-ribose) polymerase-1 gene ablation protects mice from ischemic renal injury. 1549 43

Acute Renal Failure (ARF) is the most costly kidney disease in hospitalized patients and remains as a serious problem in clinical medicine. The mortality rate among ARF patients remains around 50% and no pharmaceutical agents are currently available to improve its clinical outcome. Although several successful therapeutic approaches have been developed in animal models of the disease, translation of the results to clinical ARF remains elusive. Understanding the cellular and molecular mechanisms of vascular and tubular dysfunction in ARF is important for developing acceptable therapeutic interventions. Following an ischemic episode, cells of the affected nephron undergo necrotic and/or apoptotic cell death. Necrotic cell death is widely considered to be a futile process that cannot be modulated by pharmacological means as opposed to apoptosis. However, recent reports from various laboratories including ours indicate that inhibition or absence of poly(ADP)-ribose polymerase (PARP), one of the molecules involved in cell death, provides remarkable protection in disease models such as stroke, myocardial infarction and renal ischemia which are characterized predominantly by necrotic type of cell death. Overactivation of PARP in conditions such as ischemic renal injury leads to cellular depletion of its substrate NAD+ and consequently ATP. The severely compromised cellular energetic state induces acute cell injury and diminishes renal functions. PARP activation also enhances the expression of proinflammatory agents and adhesion molecules in ischemic kidneys. Pharmacological inhibition and gene ablation of PARP-1 decreased energy depletion, inflammatory response and improved renal functions in the setting renal ischemia/reperfusion injury. The biochemical pathways and the cellular and molecular mechanisms mediated by PARP-1 activation in eliciting the energy depletion and inflammatory responses in ischemic kidney are not fully elucidated. Dissecting the molecular mechanisms by which PARP activation contributes to oxidant-induced cell death will provide new strategies to interfere in those pathways to modulate cell death in renal ischemia. The current review evaluates the experimental evidences in animal and cell culture models implicating PARP as a pathophysiological modulator of acute renal failure with particular emphasis on ischemic renal injury.
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PMID:Poly(ADP-ribose) polymerase-mediated cell injury in acute renal failure. 1591 33

The ischemia/reperfusion (I/R) model in rats allows pharmacological investigation of protective renal effects of certain agents to thereby diminish the incidence of delayed graft function (DGF). The aim of this study was to determine the effects of preconditioning with triiodothyronine (T(3)) on renal function and oxidative status in renal I/R injury. Forty male Wistar rats were preconditioned with T(3) (100 microg/kg) or control (normal saline) at 24 hours prior to 45 minutes of renal ischemia, followed by a 4-hour (groups C-4h and T(3)-4h) or 24-hour (groups C-24h and T(3)-24h) reperfusion period. We determined renal function parameters (urea, creatinine, and proteinuria), oxidative stress biomarkers in plasma (malondialdehyde [MDA], glutathione [GSH], and superoxide dismutase [SOD]), urine (hydrogen peroxide [H(2)O(2)]), and renal tissue (GSH and MDA), and poly(ADP-ribose) polymerase (PARP-1) expression. Proteinuria was significantly lower in the T(3)-treated group (4.63 +/- 1.9 vs 9.27 +/- 0.72 mg/mL/100 g body weight). Pretreated rats showed lower levels of plasma and tissue MDA and urine H(2)O(2) (50.57 +/- 1.17 vs 71.16 +/- 1.14 micromol/100 g body weight). The T(3) treatment was associated with lower postischemia GSH concentrations (3.82 +/- 1.16 vs 4.89 +/- 0.68 nmol/mg protein) and higher SOD levels at 24 hours (11.27 +/- 0.86 vs 9.92 +/- 1.77 nmol/mg protein). Preconditioning with the hormone also reduced PARP-1 tissue expression by 18% (P <or= .05). These findings suggested that preconditioning with T(3) reduced proteinuria, improved lipid peroxidation biomarkers, and increased antioxidant enzyme levels in renal I/R injury.
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PMID:Effect of preconditioning with triiodothyronine on renal ischemia/reperfusion injury and poly(ADP-ribose) polymerase expression in rats. 1971 35

The generation of reactive oxygen species (ROS) has been implicated in the pathogenesis of renal ischemia/reperfusion injury, and many other pathological conditions. DNA strand breaks caused by ROS lead to the activation of poly(ADP-ribose)polymerase-1 (PARP-1), the excessive activation of which can result in cell death. We have utilized a model in which 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a nephrotoxic and nephrocarcinogenic metabolite of hydroquinone, causes ROS-dependent cell death in human renal proximal tubule epithelial cells (HK-2), to further elucidate the role of PARP-1 in ROS-dependent cell death. TGHQ-induced ROS generation, DNA strand breaks, hyperactivation of PARP-1, rapid depletion of nicotinamide adenine dinucleotide (NAD), elevations in intracellular Ca(2+) concentrations, and subsequent nonapoptotic cell death in both a PARP- and Ca(2+)-dependent manner. Thus, inhibition of PARP-1 with PJ34 completely blocked TGHQ-mediated accumulation of poly(ADP-ribose) polymers and NAD consumption, and delayed HK-2 cell death. In contrast, chelation of intracellular Ca(2+) with BAPTA completely abrogated TGHQ-induced cell death. Ca(2+) chelation also attenuated PARP-1 hyperactivation. Conversely, inhibition of PARP-1 modulated TGHQ-mediated changes in Ca(2+) homeostasis. Interestingly, PARP-1 hyperactivation was not accompanied by the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus, a process usually associated with PARP-dependent cell death. Thus, pathways coupling PARP-1 hyperactivation to cell death are likely to be context-dependent, and therapeutic strategies designed to target PARP-1 need to recognize such variability. Our studies provide new insights into PARP-1-mediated nonapoptotic cell death, during which PARP-1 hyperactivation and elevations in intracellular Ca(2+) are reciprocally coupled to amplify ROS-induced nonapoptotic cell death.
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PMID:PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced nonapoptotic cell death. 2475 4

Renal ischemia and reperfusion (I/R) injury, which commonly occurs in kidney transplantation, is the leading cause of acute kidney injury. Picroside II possesses a wide range of pharmacological effects, including anti-apoptosis effects. In the present study, the ability of picroside II to attenuate apoptosis in a rat model of renal I/R injury was investigated. Sprague-Dawley rats were subjected to 45 min of ischemia followed by 24 h of reperfusion. Prior to reperfusion, the rats were treated with picroside II or an equal volume of phosphate-buffered saline. It was observed that renal function was significantly improved by the treatment with picroside II. Morphological analysis indicated that picroside II markedly reduced tissue damage and the expression of cleaved caspase-3. Reverse transcription-quantitative polymerase chain reaction and western blotting revealed that the expression levels of Bax and poly(ADP-ribose) polymerase-1 (PARP-1) were upregulated in the I/R group, whereas those of Bcl-2 were downregulated. However, the treatment with picroside II inhibited these changes induced by renal I/R injury. In conclusion, picroside II has potent anti-apoptotic activity against renal I/R injury.
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PMID:Effect of picroside II on apoptosis induced by renal ischemia/reperfusion injury in rats. 2566 34