ABSTRACT
Liver X receptors (LXRs) including LXRα and LXRß are nuclear receptor transcription factors and play an important role in lipid and glucose metabolism. It has been previously reported that mice lacking LXRß but not LXRα develop a severe urine concentrating defect, likely via a central mechanism. Here we provide evidence that LXRß regulates water homeostasis through increasing aquaporin 2 (AQP2) protein levels in renal collecting ducts. LXRß-/- mice exhibited a reduced response to desmopressin (dDAVP) stimulation, suggesting that the diabetes insipidus phenotype is of both central and nephrogenic origin. AQP2 protein abundance in the renal inner medulla was significantly reduced in LXRß-/- mice but with little change in AQP2 mRNA levels. In vitro studies showed that AQP2 protein levels were elevated upon LXR agonist treatment in both primary cultured mouse inner medullary duct cells (mIMCD) and the mIMCD3 cell line with stably expressed AQP2. In addition, LXR agonists including TO901317 and GW3965 failed to induce AQP2 gene transcription but diminished its protein ubiquitination in primary cultured mIMCD cells, thereby inhibiting its degradation. Moreover, LXR activation-induced AQP2 protein expression was abolished by the protease inhibitor MG132 and the ubiquitination-deficient AQP2 (K270R). Taken together, the present study demonstrates that activation of LXRß increases AQP2 protein levels in the renal collecting ducts via a posttranscriptional mechanism. As such, LXRß represents a key regulator of body water homeostasis.
Subject(s)
Aquaporin 2/metabolism , Kidney Tubules, Collecting/metabolism , Liver X Receptors/metabolism , Protein Processing, Post-Translational , Animals , Antidiuretic Agents/pharmacology , Aquaporin 2/genetics , Cell Line , Deamino Arginine Vasopressin/pharmacology , Genotype , Kidney Concentrating Ability , Kidney Tubules, Collecting/drug effects , Liver X Receptors/deficiency , Liver X Receptors/drug effects , Liver X Receptors/genetics , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Proteasome Endopeptidase Complex/metabolism , Protein Stability , Proteolysis , Time Factors , Transfection , Ubiquitination , Up-RegulationABSTRACT
ArcGIS analysis was applied to study the content level and the spatial distribution characteristics of As and Pb in street dust of Huludao city. Geoaccumulation Indexes and Potential Ecological Risk Index technique were applied to assess the ecological risk of As and Ph. The average contents of As and Pb were 33.10 mg x kg(-1) and 533.2 mg x kg(-1), which was 4 and 25 times as high as the background value respectively. The trends for Pb and As were similar with higher concentrations near Huludao Zinc Plant (HZP). The ecological risk of As and Pb contamination in street dust were serious, and the accumulation of Pb in street dust was higher than the As.
Subject(s)
Arsenic/analysis , Dust/analysis , Environmental Pollutants/analysis , Lead/analysis , Mining , China , Environmental Monitoring/methods , Humans , Risk Assessment , ZincABSTRACT
The crystal structure of an acidic phospholipase A(2) from Ophiophagus hannah (king cobra) has been determined by molecular replacement at 2.6-A resolution to a crystallographic R factor of 20.5% (R(free)=23.3%) with reasonable stereochemistry. The venom enzyme contains an unusual "pancreatic loop." The conformation of the loop is well defined and different from those in pancreas PLA(2), showing its structural variability. This analysis provides the first structure of a PLA(2)-type cardiotoxin. The sites related to the cardiotoxic and myotoxic activities are explored and the oligomer observed in the crystalline state is described.