Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study attempted to evaluate pentoxifylline's mechanism(s) of action in the prevention of acute renal failure by examining its vascular decongestant activity in a rat model for acute renal failure and inhibitory activity of nitric oxide release from activated macrophage-like (RAW 264.7 cells) and murine mammary adenocarcinoma (EMT-6 cells) cell lines. Radiolabeled chromium-erythrocytes were injected intravenously into all rats. Following occlusion of the left kidney for 45 minutes, rats were treated with pentoxifylline or normal saline. The medulla of the left (ischaemic) kidney had significantly higher radioactive counts than the right (control kidney) following an intravenous dose of normal saline. The medulla to whole blood radioactivity ratio of the left kidney was significantly greater than for the right (control) kidney. Animals administered intravenous pentoxifylline (5 mg/kg) had significantly lower radioactive counts in the medulla of the left (ischaemic) kidney than animals administered intravenous normal saline. No differences in radioactivity counts in the medulla of the left (ischaemic) kidney were observed when animals received intraperitoneal pentoxifylline (45 mg/kg) versus normal saline. In a second set of experiments the nitrite synthesis and percent cytotoxicity of pentoxifylline- and dexamethasone-treated cells were determined. Pentoxifylline at concentrations of 4 mM and 8 mM significantly decreased nitrite synthesis in RAW 264.7 cells, and at pentoxifylline concentrations of 2 mM, 4 mM, and 8 mM in EMT-6 cells compared to untreated cells. Dexamethasone at a concentration of 1 microM decreased nitrite synthesis in RAW 264.7 and EMT-6 cells compared to untreated cells. Pentoxifylline at concentrations of 0.5 mM through 8 mM significantly decreased cytotoxicity in RAW 264.7 and EMT-6 cells compared to untreated cells. Dexamethasone at a concentration of 1 microM decreased cytotoxicity in RAW 264.7 and EMT-6 cells compared to untreated cells. These finding suggest that pentoxifylline's ability to prevent acute renal failure may be a consequence of reduced vascular congestion and inhibition of nitric oxide release from activated macrophages.
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PMID:Nephroprotective mechanism(s) of pentoxifylline: reduction of erythrocyte-mediated vascular congestion and inhibition of nitric oxide release. 888 51

A 58-year-old woman with chronic myeloid leukemia (CML), and previous intolerance to interferon was treated with the BCR-ABL tyrosine kinase protein inhibitor imatinib mesylate. Coincidentally, with the start of treatment, the patient developed acute renal failure, with acute tubular necrosis being observed on histopathology. Imatinib was stopped and three hemodialysis sessions were performed, which was followed by a progressive improvement of the renal function and normalization of the urine output. One year later the patient still has mild chronic renal failure and remains in chronic phase of CML on hydroxyurea treatment.
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PMID:Acute renal failure secondary to imatinib mesylate treatment in chronic myeloid leukemia. 1291 79

Renal ischemia/reperfusion injury (IRI) is an important cause of acute renal failure. Cellular and molecular responses of the kidney to IRI are complex and not fully understood. beta1 integrins localize to the basal surface of tubular epithelium interacting with extracellular matrix components of the basal membrane, including collagen IV. Whether preservation of tubular epithelium integrity could be a therapeutic approach for IRI was assessed. The effects of HUTS-21 mAb administration, which recognizes an activation-dependent epitope of beta1 integrins, in a rat model of IRI were investigated. Preischemic HUTS-21 administration resulted in the preservation of renal functional and histopathologic parameters. Analyses of activated beta1 integrins expression and focal adhesion kinase phosphorylation suggest that its deactivation after IRI was prevented by HUTS-21 treatment. Moreover, HUTS-21 impaired the inflammatory response in vivo, as indicated by inhibition of proinflammatory mediators and the absence of infiltrating cells. Ex vivo adhesion assays using reperfused kidneys revealed that HUTS-21 induced a significant increase of epithelial cell attachment to collagen IV. In conclusion, the data provide evidence that HUTS-21 has a protective effect in renal IRI, preventing tubular epithelial cell detachment by preserving activated beta1 integrins functions.
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PMID:Renal ischemia/reperfusion injury: functional tissue preservation by anti-activated {beta}1 integrin therapy. 1559 Jul 58

Ste20-like kinase, SLK, a germinal center kinase found in kidney epithelial cells, signals to promote apoptosis. Expression of SLK mRNA and protein and kinase activity are increased during kidney development and recovery from ischemic acute renal failure. The 3'-untranslated region (3'-UTR) of SLK mRNA contains multiple adenine and uridine-rich elements, suggesting that 3'-UTR may regulate mRNA stability. This was confirmed in COS cell transient transfection studies, which showed that expression of the SLK open-reading frame plus 3'-UTR mRNA was reduced by 35% relative to the open-reading frame alone. To further characterize the SLK-3'-UTR, this nucleotide sequence was subcloned downstream of enhanced green fluorescent protein (EGFP) cDNA. In COS, 293T, and glomerular epithelial cells, expression of EGFP mRNA and protein was markedly reduced in the presence of the SLK-3'-UTR. After transfection and subsequent addition of actinomycin D, EGFP mRNA remained stable in cells for at least 6 h, whereas EGFP-SLK-3'-UTR mRNA decayed with a half-life of approximately 4 h. A region containing five AUUUA motifs within the SLK-3'-UTR destabilized EGFP mRNA. Deletion of this region from the SLK-3'-UTR, in part, restored mRNA stability. By UV cross-linking and SDS-PAGE, the SLK-3'-UTR bound to protein(s) of approximately 30 kDa in extracts of COS cells, glomerular epithelial cells, and kidney. Cotransfection of HuR (a RNA binding protein of approximately 30 kDa) increased the steady-state mRNA level of EGFP-SLK-3'-UTR but not EGFP. Thus the SLK-3'-UTR may interact with kidney RNA-binding proteins to regulate expression of SLK mRNA during kidney development and after ischemic injury.
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PMID:The 3'-untranslated region of the Ste20-like kinase SLK regulates SLK expression. 1700 24

A 30-year-old HIV-infected intravenous drug user presented with sepsis, acute renal failure, oedema, proteinuria and iron deficiency anaemia. After extensive investigation, a diagnosis of reactive systemic AA (amyloid, serum amyloid A protein) amyloidosis was made on the basis of renal, gastric and duodenal biopsies.
Int J STD AIDS 2007 May
PMID:Renal and gastrointestinal amyloidosis in an HIV-infected injection drug user. 1752 3

Dasatinib is a second-generation tyrosine kinase inhibitor that is approved for the treatment of imatinib-resistant or imatinib-intolerant chronic myeloid leukemia. It has a 325 times stronger in vitro activity against to native BCR-ABL when comparing with imatinib. Little is known about the effects of dasatinib on renal function. A literature review revealed only one case with imatinib-resistant chronic myeloid leukemia that developed renal failure after being placed on dasatinib therapy. Here we report a patient with imatinib-resistant chronic myeloid leukemia who developed gastroenteritis and acute renal failure after a short time from the initiation of dasatinib therapy. After dasatinib interruption, these side effects resolved completely in days. In summary, dasatinib is a potent drug in the treatment of chronic myeloid leukemia, but close clinical monitoring and the timely interruption of the therapy in patients who developed acute renal failure are warranted.
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PMID:Acute renal failure under dasatinib therapy. 2011 82

Chronic myelogenous leukemia (CML) is a myeloproliferative disease that originates in abnormal pluripotent bone marrow stem cells and it is consistently associated with the Philadelphia chromosome and/or BCR/ ABL fusion gene. Renal infiltration of leukemic cells is relatively rare in CML and is associated with renal impairment. We describe a patient who developed acute renal failure by tubulointerstitial nephropathy during treatment with imatinib mesylate for CML. The acute kidney injury was subsequently found to be due to direct leukemic infiltration. Treatment with hydroxycarbamide and prednisolone resulted in stabilization of the renal function for approximately 4 months. Leukemic infiltration into the kidney should always be considered when a patient with CML presents with renal impairment, regardless of the clinical stage, as the renal failure often responds well to chemotherapy.
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PMID:Acute kidney injury presenting a feature of leukemic infiltration during therapy for chronic myelogenous leukemia. 2055 31

The expression and activation of the Ste20-like kinase, SLK, is increased during renal development and recovery from ischemic acute renal failure. SLK promotes apoptosis, and during renal injury and repair, transcriptional induction or posttranscriptional control of SLK may, therefore, regulate cell survival. SLK contains protein interaction (coiled-coil) domains, suggesting that posttranslational homodimerization may also modulate SLK activity. We therefore expressed coiled-coil regions in the C-terminal domain of SLK as fusion proteins and demonstrated their homodimerization. By gel-filtration chromatography, endogenous and heterologously expressed SLK were detected in a macromolecular protein complex. To test the role of homodimerization in kinase activation, we constructed a fusion protein consisting of the SLK catalytic domain (amino acids 1-373) and a modified FK506 binding protein, Fv (Fv-SLK 1-373). Addition of AP20187 (an analog of FK506) enhanced the homodimerization of Fv-SLK 1-373. In an in vitro kinase assay, the dimeric Fv-SLK 1-373 displayed greater kinase activity than the monomeric form. In cells expressing Fv-SLK 1-373, homodimerization increased activation-specific phosphorylation of the proapoptotic kinases, c-Jun N-terminal kinase and p38 kinase. Compared with the monomer, dimeric Fv-SLK 1-373 enhanced the activation of a Bax promoter-luciferase reporter. Finally, expression of Fv-SLK 1-373 induced apoptosis, and the effect was increased by homodimerization. Thus the activity, downstream signaling, and functional effects of SLK are enhanced by dimerization of the kinase domain.
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PMID:Activity of the Ste20-like kinase, SLK, is enhanced by homodimerization. 2167 49

We describe a case of rhabdomyolysis associated with trimethoprim-sulphamethoxazole (TMP-SMZ) in a HIV-infected patient. A 33-year-old African American man with newly diagnosed AIDS initially presented with persistent, high-grade fevers suspected to be TMP-SMZ-related drug fever. The antibiotic was discontinued while in the hospital, but the patient was restarted on TMP-SMZ following discharge. Two days later, he returned to the hospital with severe muscle pain, acute renal failure and a significantly elevated creatine phosphokinase consistent with rhabdomyolysis. The patient gradually improved following discontinuation of TMP-SMZ.
Int J STD AIDS 2011 Jul
PMID:Trimethoprim-sulphamethoxazole-associated rhabdomyolysis in an HIV-infected patient. 2172 64

Disseminated Mycobacterium simiae is a rare opportunistic infection reported most commonly in advanced human immunodeficiency virus (HIV) infection. Treatment can be further complicated by the occurrence of severe immune reconstitution inflammatory syndrome (IRIS). We present the first case of disseminated multi-drug-resistant M. simiae in the setting of advanced HIV, complicated by IRIS in the form of granulomatous interstitial nephritis causing acute renal failure. This case highlights the importance of recognizing rare complications of IRIS, as delays in therapy can be life threatening.
Int J STD AIDS 2020 Aug
PMID:Granulomatous interstitial nephritis in the setting of disseminated Mycobacterium simiae: a rare presentation of immune reconstitution inflammatory syndrome. 3260 2


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