Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephrotic syndrome is often accompanied by sodium retention and generalized edema. We hypothesize that dysregulation of the epithelial sodium channel (ENaC) and/or of sodium (co)transporters may be responsible for the increased sodium retention associated with HgCl(2)-induced nephropathy. In addition, we examined the hypothesis that the expression of type 2 11beta-hydroxysteroid dehydrogenase (11betaHSD2) is reduced, contributing to the enhanced mineralocorticoid activity. Membranous nephropathy was induced in Brown Norway rats by repeated injections of HgCl(2) (1 mg/kg sc), whereas the control group received only vehicle. After 13 days of treatment, the abundance of ENaC subunits, sodium (co)transporters, and 11betaHSD2 in the kidney was examined by immunoblotting and immunohistochemistry. HgCl(2) treatment induced marked proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and ascites. The protein abundance of alpha-ENaC was increased in the cortex/outer stripe of outer medulla (OSOM) and inner stripe of the outer medulla (ISOM). The protein abundances of beta-ENaC and gamma-ENaC were decreased in the cortex/OSOM while increased in the ISOM. Immunoperoxidase microscopy demonstrated increased targeting of ENaC subunits to the apical plasma membrane in the distal convoluted tubule, connecting tubule, and cortical and medullary collecting duct segments. Moreover, 11betaHSD2 abundance was decreased in cortex/OSOM and ISOM. The protein abundances of type 3 Na/H exchanger (NHE3), Na-K-2Cl cotransporter (NKCC2), and thiazide-sensitive Na-Cl cotransporter (NCC) were decreased. Moreover, the abundance of the alpha-1 subunit of the Na-K-ATPase was decreased in the cortex/OSOM and ISOM but remained unchanged in the inner medulla. These results suggest that increased apical targeting of ENaC subunits combined with diminished abundance of 11betaHSD2 may contribute to sodium retention associated with HgCl(2)-induced nephrotic syndrome. The decreased abundance of NHE3, NKCC2, NCC, and Na-K-ATPase may play a compensatory role in promoting sodium excretion.
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PMID:Increased apical targeting of renal ENaC subunits and decreased expression of 11betaHSD2 in HgCl2-induced nephrotic syndrome in rats. 1618 94

Renal sodium reabsorption is a key determinant of final urine concentration. Our aim was to determine whether differences existed between aged and young rats in their response to water restriction with regard to the regulation of abundance of any of the major distal renal sodium transporter proteins. Male Fisher 344 x Brown Norway (F344 x BN) rats of 3-, 10-, 24-, or 31 months of age (3M, 10M, 24M, or 31M) were either water restricted (WR) for 5 days or control (ad libitum water). Major renal sodium transporters and channel subunits were evaluated by immunoblotting and immunohistochemistry. Age did not significantly affect plasma arginine vasopressin or aldosterone levels, but renin activity was only 8% in 31M-WR rats relative to 3M-WR (P<0.05). Extreme aging (31M) led to decreased outer medullary abundance of the bumetanide-sensitive Na-K-2Cl cotransporter and decreased cortical abundance of the beta- and gamma-subunits (70-kDa band) of the epithelial sodium channel (ENaC) (P<0.05). Water restriction significantly (P<0.05) increased the abundance of Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC) across ages. However, these increases were significantly blunted as rats aged. Mean band densities were increased in WR rats (relative to age controls) by 54 and 106% at 3M, but only 25 and 29% at 24M and 0 and 6% at 31M for NKCC2 and NCC, respectively. Aged F344 x BN rats have reduced basal distal tubular renal sodium transporter abundances and blunted upregulation during water restriction, which may contribute to decreased urinary concentrating capacity.
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PMID:Renal ENaC subunit, Na-K-2Cl and Na-Cl cotransporter abundances in aged, water-restricted F344 x Brown Norway rats. 1640 20

Brown spider venom phospholipase-D belongs to a family of toxins characterized as potent bioactive agents. These toxins have been involved in numerous aspects of cell pathophysiology including inflammatory response, platelet aggregation, endothelial cell hyperactivation, renal disorders, and hemolysis. The molecular mechanism by which these toxins cause hemolysis is under investigation; literature data have suggested that enzyme catalysis is necessary for the biological activities triggered by the toxin. However, the way by which phospholipase-D activity is directly related with human hemolysis has not been determined. To evaluate how brown spider venom phospholipase-D activity causes hemolysis, we examined the impact of recombinant phospholipase-D on human red blood cells. Using six different purified recombinant phospholipase-D molecules obtained from a cDNA venom gland library, we demonstrated that there is a correlation of hemolytic effect and phospholipase-D activity. Studying recombinant phospholipase-D, a potent hemolytic and phospholipase-D recombinant toxin (LiRecDT1), we determined that the toxin degrades synthetic sphingomyelin (SM), lysophosphatidylcholine (LPC), and lyso-platelet-activating factor. Additionally, we determined that the toxin degrades phospholipids in a detergent extract of human erythrocytes, as well as phospholipids from ghosts of human red blood cells. The products of the degradation of synthetic SM and LPC following recombinant phospholipase-D treatments caused hemolysis of human erythrocytes. This hemolysis, dependent on products of metabolism of phospholipids, is also dependent on calcium ion concentration because the percentage of hemolysis increased with an increase in the dose of calcium in the medium. Recombinant phospholipase-D treatment of human erythrocytes stimulated an influx of calcium into the cells that was detected by a calcium-sensitive fluorescent probe (Fluo-4). This calcium influx was shown to be channel-mediated rather than leak-promoted because the influx was inhibited by L-type calcium channel inhibitors but not by a T-type calcium channel blocker, sodium channel inhibitor or a specific inhibitor of calcium activated potassium channels. Finally, this inhibition of hemolysis following recombinant phospholipase-D treatment occurred in a concentration-dependent manner in the presence of L-type calcium channel blockers such as nifedipine and verapamil. The data provided herein, suggest that the brown spider venom phospholipase-D-induced hemolysis of human erythrocytes is dependent on the metabolism of membrane phospholipids, such as SM and LPC, generating bioactive products that stimulate a calcium influx into red blood cells mediated by the L-type channel.
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PMID:The relationship between calcium and the metabolism of plasma membrane phospholipids in hemolysis induced by brown spider venom phospholipase-D toxin. 2159 Jul 5

Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.
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PMID:Predictive validity of a MK-801-induced cognitive impairment model in mice: implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically. 2426 64