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)

Mxi2 is one of three known alternative spliced forms of the stress-activated mitogen-activated protein kinase p38 (CSBP). Mxi2 was originally identified as a Max-interacting protein and is the smallest member of the family of stress-activated kinases isolated to date. Mxi2 lacks most of the XI domain found in p38 and instead has a distinct COOH-terminal sequence of 17 amino acids. Here we present the genomic structure of the Mxi2/p38 locus on human chromosome 6q21.2/21.3 and establish the origin of the three spliced forms of p38. Using Mxi2-specific antibodies in mouse organs, we found the Mxi2 protein to be present exclusively in the kidney. Mxi2 is present predominantly in the distal tubule of the nephron and the level of the protein decreased during kidney ischemia-reperfusion. Stress signals or other known activators of the p38 pathway including MAP kinase-kinase 3 and MAP kinase-kinase 6 did not induce the kinase activity of Mxi2 using ATF-2 as a substrate. With the use of hybrid proteins encoding different portions of Mxi2 and p38 polypeptides, the different properties of Mxi2 can be assigned to its unique COOH terminus.
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PMID:Mxi2, a splice variant of p38 stress-activated kinase, is a distal nephron protein regulated with kidney ischemia. 1075 26

Ischemia followed by reperfusion has a number of clinically significant consequences. A number of pathophysiological processes appear to be involved in ischemia/reperfusion (I/R) injury. The mitogen activated protein kinases (MAPK) are integral components of the parallel MAP kinase cascades activated in response to a variety of cellular stress inducing ischemia/ATP depletion and inflammatory cytokines. Many studies suggest that members of the MAP kinase family in particular Jun N-terminal kinase (JNK) are activated in kidney following ischemia/reperfusion of this tissue. The present study underlines the therapeutic potential of the combination of N-acetyl cysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor and phosphoramidon (P), an endothelin-1 converting enzyme inhibitor in ameliorating the MAPK induced damage during renal ischemia/reperfusion injury. Our previous results showed that 90 min of ischemia followed by reperfusion caused very severe injury and that the untreated animals had 100% mortality after the 3rd day whereas there was improved renal function and 100% survival of animals in the three drug combination treatment group. The present study, mainly on tissue sections, further supports the protection provided by the triple drug therapy. A higher degree of expression of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular signal regulated kinases (ERKs) can be seen in kidneys subjected to ischemia/reperfusion insult. Pretreatment with a combination of N-acetyl cysteine, sodium nitroprusside, and phosphoramidon completely inhibits all three classes of MAPK and ameliorates AP-1 whereas individual or a combination of any two drugs is not as effective.
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PMID:Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon. 1248 68

Reactivation of latent human cytomegalovirus is of significant concern in immunocompromised transplant patients and is likely to occur through transcriptional activation of immediate early (ie) gene expression through mechanisms that are not well understood. TNF-mediated activation of NF-kappaB has been proposed to be one pathway leading to transcriptional activation of CMV ie gene expression. Using transgenic mice carrying a lacZ reporter gene under the control of the HCMV major ie promoter/enhancer (MIEP-lacZ mice) and MIEP-lacZ mice deficient in TNF receptor 1 and TNF receptor 2 (MIEP-lac Z TNFR DKO mice), we demonstrate that renal ischemia/reperfusion (I/R) injury activates the HCMV enhancer independently of TNF. Induction of MIEP-lacZ expression was preceded by TNFR-independent formation of reactive oxygen species (ROS), weak and transient activation of NF-kappaB and strong and sustained activation of AP-1. Our studies show that, in addition to TNF-mediated signaling, TNF-independent signaling induced by I/R injury can contribute to the activation of the HCMV enhancer. This likely occurs through ROS-mediated activation of AP-1. Targeting MAP kinase signaling pathways as well as NF-kappaB may be of therapeutic value in patients with CMV infection.
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PMID:Renal ischemia/reperfusion injury activates the enhancer domain of the human cytomegalovirus major immediate early promoter. 1594 18

Renal ischemia-reperfusion injury results in oxidative stress-induced alterations in barrier function. Activation of the mitogen-activated protein (MAP) kinase pathway during recovery from oxidative stress may be an effector of oxidant-induced tight junction reorganization. We hypothesized that tight junction composition and barrier function would be perturbed during recovery from oxidative stress. We developed a model of short-term H(2)O(2) exposure followed by recovery using Madin Darby canine kidney (MDCK II) cells. H(2)O(2) perturbs barrier function without a significant cytotoxic effect except in significant doses. ERK-1/2 and p38, both enzymes of the MAP kinase pathway, were activated within minutes of exposure to H(2)O(2). Transient exposure to H(2)O(2) produced a biphasic response in the transepithelial electrical resistance (TER). An initial drop in TER at 6 h was followed by a significant increase at 24 h. Inhibition of ERK-1/2 activation attenuated the increase in TER observed at 24 h. Expression of occludin initially decreased, followed by partial recovery at 24 h. In contrast, claudin-1 levels decreased and failed to recover at 24 h. Claudin-2 levels were markedly decreased at 24 h; however, inhibition of ERK-1/2 activation was protective. Occludin and claudin-1 localization at the apical membrane on immunofluorescence images was fragmented at 6 h after H(2)O(2) exposure with subsequent recovery of appropriate localization by 24 h. MDCK II cell recovery after H(2)O(2) exposure is associated with functional and structural modifications of the tight junction that are mediated in part by activation of the MAP kinase enzymes ERK-1/2 and p38.
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PMID:Remodeling of the tight junction during recovery from exposure to hydrogen peroxide in kidney epithelial cells. 1973 32

The receptor for advanced glycation end-products (RAGE), a multiligand receptor of the immunoglobulin superfamily, takes part in various inflammatory processes. The role of this receptor in the context of intercellular communication, like nanotube (NT)-mediated interaction, is largely unknown. Here, we use cell cultures of human and murine peritoneal mesothelial cells as well as murine kidneys from wild-type and RAGE knockout mouse models to assess the role of RAGE in NT formation and function. We show that loss of RAGE function results in reduced NT numbers under physiological conditions and demonstrate the involvement of MAP kinase signaling in NT formation. Additionally, we show for the first time the existence of NTs in murine kidney tissue and confirm the correlation of RAGE expression and NT numbers. Under elevated oxidative stress conditions like renal ischemia or peritoneal dialysis, we demonstrate that RAGE absence does not prevent NT formation. Rather, increased NT numbers and attenuated kidney tissue damage could be observed, indicating that, depending on the predominant conditions, RAGE affects NT formation with implications for cellular communication.
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PMID:The receptor for advanced glycation end-products (RAGE) plays a key role in the formation of nanotubes (NTs) between peritoneal mesothelial cells and in murine kidneys. 2487 Sep 78

Renal ischemia-reperfusion (I/R) injury is a predominant cause of acute kidney injury (AKI), the pathologic mechanism of which is highly complex involving reactive oxygen species (ROS) accumulation, inflammatory response, autophagy, apoptosis as well as endoplasmic reticulum (ER) stress. Fibroblast growth factor 10 (FGF10), as a multifunctional growth factor, plays crucial roles in embryonic development, adult homeostasis, and regenerative medicine. Herein, we investigated the molecular pathways underlying the protective effect of FGF10 on renal I/R injury using Sprague-Dawley rats. Results showed that administration of FGF10 not only effectively inhibited I/R-induced activation of Caspase-3 and expression of Bax, but also alleviated I/R evoked expression of ER stress-related proteins in the kidney including CHOP, GRP78, XBP-1, and ATF-4 and ATF-6. The protective effect of FGF10 against apoptosis and ER stress was recapitulated by in vitro experiments using oxidative damaged NRK-52E cells induced by tert-Butyl hydroperoxide (TBHP). Significantly, U0126, a selective noncompetitive inhibitor of MAP kinase kinases (MKK), largely abolished the protective role of FGF10. Taken together, both in vivo and in vitro experiments indicated that FGF10 attenuates I/R-induced renal epithelial apoptosis by suppressing excessive ER stress, which is, at least partially, mediated by the activation of the MEK-ERK1/2 signaling pathway. Therefore, our present study revealed the therapeutic potential of FGF10 on renal I/R injury.
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PMID:Fibroblast Growth Factor 10 Attenuates Renal Damage by Regulating Endoplasmic Reticulum Stress After Ischemia-Reperfusion Injury. 3211 15