Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sildenafil is the first commercially available selective inhibitor of phosphodiesterase-5 (PDE5) and is widely used for the treatment of erectile dysfunction. In recent years, investigations of the role of sildenafil in cardioprotection in animal models have received considerable interest. We evaluated whether sildenafil can attenuate cisplatin-induced nephrotoxicity in a rat experimental model. Male Sprague-Dawley rats were divided into five groups: control rats, sildenafil-control rats, cisplatin-injected rats (5 mg kg(-1) IP, single dose), sildenafil-treated cisplatin-injected rats (0.4 mg kg(-1), daily), and sildenafil+NG-nitro-l-arginine methyl ester hydrochloride (l-NAME)-treated rats. The molecular, functional, and structural parameters of the kidney were measured. At 96 h after cisplatin injection, serum levels of creatinine were lower in rats treated with both sildenafil+cisplatin compared with rats treated with cisplatin alone, and renal iNOS and eNOS expression was significantly higher in sildenafil+cisplatin-treated rats compared with rats treated with cisplatin alone (all P<0.05). Renal Bax gene and protein expression was significantly higher in cisplatin-treated rats compared with control rats, and sildenafil treatment significantly reduced the levels of Bax and increased the renal Bax/Bcl-2 ratio (P<0.05). Sildenafil treatment also reduced renal caspase-3 activation and TUNEL-positive apoptotic cells. These data suggest that sildenafil attenuates experimental cisplatin-induced nephrotoxicity by preventing apoptosis.
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PMID:Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. 1915 27

Prolonged ischemia amplified iscehemia/reperfusion (IR) induced renal apoptosis and autophagy. We hypothesize that ischemic conditioning (IC) by a briefly intermittent reperfusion during a prolonged ischemic phase may ameliorate IR induced renal dysfunction. We evaluated the antioxidant/oxidant mechanism, autophagy and apoptosis in the uninephrectomized Wistar rats subjected to sham control, 4 stages of 15-min IC (I15 x 4), 2 stages of 30-min IC (I30 x 2), and total 60-min ischema (I60) in the kidney followed by 4 or 24 hours of reperfusion. By use of ATP assay, monitoring O2-. amounts, autophagy and apoptosis analysis of rat kidneys, I60 followed by 4 hours of reperfusion decreased renal ATP and enhanced reactive oxygen species (ROS) level and proapoptotic and autophagic mechanisms, including enhanced Bax/Bcl-2 ratio, cytochrome C release, active caspase 3, poly-(ADP-ribose)-polymerase (PARP) degradation fragments, microtubule-associated protein light chain 3 (LC3) and Beclin-1 expression and subsequently tubular apoptosis and autophagy associated with elevated blood urea nitrogen and creatinine level. I30 x 2, not I15 x 4 decreased ROS production and cytochrome C release, increased Manganese superoxide dismutase (MnSOD), Copper-Zn superoxide dismutase (CuZnSOD) and catalase expression and provided a more efficient protection than I60 against IR induced tubular apoptosis and autophagy and blood urea nitrogen and creatinine level. We conclude that 60-min renal ischemia enhanced renal tubular oxidative stress, proapoptosis and autophagy in the rat kidneys. Two stages of 30-min ischemia with 3-min reperfusion significantly preserved renal ATP content, increased antioxidant defense mechanisms and decreased ischemia/reperfusion enhanced renal tubular oxidative stress, cytosolic cytochrome C release, proapoptosis and autophagy in rat kidneys.
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PMID:Ischemic conditioning by short periods of reperfusion attenuates renal ischemia/reperfusion induced apoptosis and autophagy in the rat. 1927 87

Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.
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PMID:Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats. 1947 86

Free radicals are involved in pathophysiology of ischemia/reperfusion injury (IRI). Melatonin is a potent scavenger of reactive oxygen and nitrogen species. Thus, this study was designed to elucidate its effects in a model of rat kidney transplantation. Twenty Lewis rats were randomly divided into 2 groups (n = 10 animals each). Melatonin (50 mg/kg BW) dissolved in 5 mL milk was given to one group via gavage 2 hr before left donor nephrectomy. Controls were given the same volume of milk only. Kidney grafts were then transplanted into bilaterally nephrectomized syngeneic recipients after 24 hr of cold storage in Histidine-Tryptophan-Ketoglutarate solution. Both graft function and injury were assessed after transplantation through serum levels of blood urea nitrogen (BUN), creatinine, transaminases, and lactate dehydrogenase (LDH). Biopsies were taken to evaluate tubular damage, the enzymatic activity of superoxide dismutase (SOD) and lipid hydroperoxide (LPO), and the expression of NF-kBp65, inducible nitric oxide synthase (iNOS), caspase-3 as indices of oxidative stress, necrosis, and apoptosis, respectively. Melatonin improved survival (P < 0.01) while decreasing BUN, creatinine, transaminases, and LDH values up to 39-71% (P < 0.05). Melatonin significantly reduced the histological index for tubular damage, induced tissue enzymatic activity of SOD while reducing LPO. At the same time, melatonin down-regulated the expression of NF-kBp65, iNOS, and caspase-3. In conclusion, donor preconditioning with melatonin protected kidney donor grafts from IRI-induced renal dysfunction and tubular injury most likely through its anti-oxidative, anti-apoptotic and NF-kB inhibitory capacity.
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PMID:Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-kB and apoptosis after experimental kidney transplantation. 1955 59

Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the United States and Europe. Approximately 30-40% of patients with type I and 15% with type II diabetes mellitus develop end ESRD. The study was designed to evaluate the impact of sesamol on renal function and renoinflammatory cascade in streptozotocin (STZ)-induced diabetes. STZ-induced diabetic rats were treated with sesamol (2, 4, and 8 mg/kg/day; po) or with vehicle from the fifth to eighth weeks. After 8 weeks, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine, and urea clearance were measured. Cytoplasmic and nuclear fractions of kidney were prepared for the quantification of oxidative-nitrosative stress (lipid peroxidation, superoxide dismutase, catalase, nonprotein thiols, total nitric oxide), tumor necrosis factor-alpha (TNF-alpha), tissue growth factor-1 beta (TGF-beta1), p65 subunit of NFkappabeta, and caspase-3. After 8 weeks of STZ injection, the rats produced significant alteration in renal function, increased oxidative-nitrosative stress, TNF-alpha, TGF-beta1, caspase-3 activity in cytoplasmic lysate, and active p65 subunit of NFkappabeta in nuclear lysate of kidney of diabetic rats. Interestingly, co-administration of sesamol significantly and dose-dependently prevented biochemical and molecular changes associated with diabetes. Moreover, diabetic rats treated with insulin-sesamol combination produced more pronounced effect on molecular parameters as compared to their respective groups. The data reveal that sesamol modulates the release of profibrotic cytokines, oxidative stress, ongoing chronic inflammation, and apoptosis and thus exerts a marked renoprotective effect.
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PMID:Attenuation of renoinflammatory cascade in experimental model of diabetic nephropathy by sesamol. 1960 60

Prostacyclin and peroxisome proliferator-activated receptors (PPAR) protect against ischemia-reperfusion (I/R) injury by the induction of an anti-inflammatory pathway. In this study, we examined the prostacyclin-enhanced protective effect of PPARalpha in I/R-induced kidney injury. PPAR-alpha reduced the NF-kappaB-induced overexpression of TNF-alpha and apoptosis in cultured kidney cells. In a murine model, pretreating wild-type (WT) mice with a PPAR-alpha activator, docosahexaenoic acid (DHA), significantly reduced I/R-induced renal dysfunction (lowered serum creatinine and urea nitrogen levels), apoptotic responses (decreased apoptotic cell number and caspase-3, -8 activation), and NF-kappaB activation. By comparison, I/R-induced injury was exacerbated in PPAR-alpha knockout mice. This indicated that PPAR-alpha attenuated renal I/R injury via NF-kappaB-induced TNF-alpha overexpression. Overexpression of prostacyclin using an adenovirus could also induce PPAR-alpha translocation from the cytosol into the nucleus to inhibit caspase-3 activation. This prostacyclin/PPAR-alpha pathway attenuated TNF-alpha promoter activity by binding to NF-kappaB. Using a cAMP inhibitor (CAY10441) and a prostacyclin receptor antibody, we also found that there was another prostacyclin/IP receptor/cAMP pathway that could inhibit TNF-alpha production. Taken together, our results demonstrate for the first time that prostacyclin induces the translocation of PPAR-alpha from the cytosol into the nucleus and attenuates NF-kappaB-induced TNF-alpha activation following renal I/R injury. Treatments that can augment prostacyclin, PPAR-alpha, or the associated signaling pathways may ameliorate conditions associated with renal I/R injury.
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PMID:Prostacyclin-induced peroxisome proliferator-activated receptor-alpha translocation attenuates NF-kappaB and TNF-alpha activation after renal ischemia-reperfusion injury. 1964 Sep 4

Diabetic nephropathy is a common cause for end-stage renal disease. Present study investigated the beneficial role of arjunolic acid (AA) against streptozotocin (STZ) induced diabetic nephropathy in rats. Diabetic renal injury was associated with increased kidney weight to body weight ratio, glomerular area and volume, blood glucose (hyperglycemia), urea nitrogen and serum creatinine. This nephro pathophysiology increased the productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS), enhanced lipid peroxidation, protein carbonylation and decreased intracellular antioxidant defense in the kidney tissue. In addition, hyperglycemia activates polyol pathway by increasing aldose reductase (AR) with a concomitant reduction in Na+-K+-ATPase activity. Investigating the oxidative stress responsive signaling cascades, we found the activation of PKCdelta, PKCvarepsilon, MAPKs and NF-kappaB (p65) in the renal tissue of the diabetic animals. Furthermore, hyperglycemia disturbed the equilibrium between the pro and anti-apoptotic members of Bcl-2 family of proteins as well as reduced mitochondrial membrane potential, elevated the concentration of cytosolic cytochrome C and caspase-3 activity. Treatment of AA effectively ameliorated diabetic renal dysfunctions by reducing oxidative as well as nitrosative stress and deactivating the polyol pathways. Histological studies also support the experimental findings. Results suggest that AA might act as a beneficial agent against the renal dysfunctions developed in STZ-induced diabetes.
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PMID:Prophylactic role of arjunolic acid in response to streptozotocin mediated diabetic renal injury: activation of polyol pathway and oxidative stress responsive signaling cascades. 1968 44

Acetaminophen (APAP) causes acute and chronic renal failure. The mechanisms leading to hepatic injury have been extensively studied, but the molecular mechanisms regarding APAP-induced nephro-toxicity are poorly defined. In earlier studies, we have demonstrated that arjunolic acid (AA) possesses protective roles against chemically induced organ pathophysiology. The purpose of the present study was to explore whether AA plays any protective role against APAP induced acute renal toxicity; and if so, what pathways it utilizes for the mechanism of its protective action. Exposure of rats with a nephro-toxic dose of APAP altered a number of biomarkers (like blood urea nitrogen and serum creatinine levels, etc.) related to renal oxidative stress, decreased antioxidant activity, elevated renal tumor necrosis factor-alpha and nitric oxide levels. AA treatment both pre- and post to APAP exposure protected the alteration of these biomarkers, compensated deficits in the antioxidant defense mechanisms, and suppressed lipid peroxidation in renal tissue. Investigating the inherent molecular signaling of this pathophysiology and its protection, we found that the mitochondrial pathway was not activated during APAP-induced cell death as no dissipation of mitochondrial membrane potential or release of cytochrome C was detected in the respective experiments. Our experimental evidence suggests that APAP-induced nephro-toxicity is a caspase-dependent process that involves activation of caspase-9 and caspase-3 in the absence of cytosolic cytochrome C release. These results provide evidence that inhibition of NO overproduction and maintenance of intracellular antioxidant status may play a pivotal role in the protective effects of AA against APAP-induced renal damage. AA represents a potential therapeutic option to protect renal tissue from the detrimental effects of acute acetaminophen overdose.
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PMID:Acetaminophen induced renal injury via oxidative stress and TNF-alpha production: therapeutic potential of arjunolic acid. 1992 64

Human cytomegalovirus (HCMV) infection is associated with a series of direct and indirect effects following renal transplantation. However, the presence of HCMV in the kidney and its relationship with acute rejection and long-term graft function remain to be fully elucidated. Sixty-two biopsies derived from 30 renal transplant recipients with signs of clinical rejection were analyzed for HCMV using a sensitive in situ DNA hybridization method. Biopsies were also subjected to staining with anti-C4d antibodies and an anti-caspase 3 antibody to detect humoral rejection and apoptosis, respectively. In 21 patients, serial serum creatinine levels over 5 years of follow-up were analyzed. HCMV DNA was detected in biopsies from 21/30 (70%) of the patients and 32/62 (52%) of the individual biopsies. HCMV DNA was detected early after transplant and was localized to renal tubule epithelial cells but not associated with apoptosis. HCMV DNAemia developed within 2 weeks of detecting HCMV DNA in the biopsy in 53% of patients. Ninety percent of patients experiencing HCMV disease had HCMV DNA in their biopsy. HCMV DNA was equally distributed between patients with or without histological evidence of acute rejection and was detected more frequently in patients with peritubular C4d deposits. Creatinine levels at 12 months post-transplant were significantly higher in patients with HCMV DNA and remained elevated over the 5 years of follow-up. HCMV DNA is frequently detected in renal tubular epithelial cells early after renal transplantation, precedes DNAemia and is associated with poor long-term graft function.
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PMID:Extensive human cytomegalovirus (HCMV) genomic DNA in the renal tubular epithelium early after renal transplantation: Relationship with HCMV DNAemia and long-term graft function. 1995 Feb 42

Delayed graft function still represents a major complication in clinical kidney transplantation. Here we tested the possibility to improve functional outcome of cold stored kidneys a posteriori by short-term hypothermic machine perfusion immediately prior to reperfusion. A total of 18 kidneys from female German Landrace pigs was flushed with Histidine-Tryptophan-Ketoglutarate solution and cold-stored for 18 h (control). Some grafts were subsequently subjected to 90 min of hypothermic reconditioning by hypothermic machine perfusion with (HR+O(2)) or without (HR-O(2)) oxygenation of the perfusate. Early graft function of all kidneys was assessed thereafter by warm reperfusion in vitro (n = 6, respectively). Renal function upon reperfusion was significantly enhanced by HR+O(2) with more than threefold increase in renal clearances of creatinine and urea. HR+O(2) also led to significantly higher urinary flow rates and abrogated the activation of caspase 3. By contrast, HR-O(2) was far less effective and only resulted in minor differences compared to control. It is derived from the present data that initial graft function can be significantly improved by 2 h of oxygenated machine perfusion after arrival of the preserved organ in the transplantation clinic.
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PMID:Hypothermic reconditioning after cold storage improves postischemic graft function in isolated porcine kidneys. 1995 72


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