title: Rosiglitazone promotes AQP2 plasma membrane expression in renal cells via a Ca-dependent/cAMP-independent mechanism.
abstract: OBJECTIVE
  Thiazolidinediones are highly beneficial in the treatment of type II diabetes. However, they are also associated with edema and increased risk of congestive heart failure. Several studies demonstrated that rosiglitazone (RGZ) increases the abundance of aquaporin-2 (AQP2) at the plasma membrane of renal cells. The aim of this study was to investigate whether RGZ might activate a transduction pathway facilitating AQP2 membrane accumulation in renal cells.
  
  
  METHODS
  We analyzed the effect of RGZ on renal AQP2 intracellular trafficking in MCD4 renal cells by confocal microscopy and apical surface biotinylation. Cytosolic Ca(2+) dynamics were measured by a video-imaging approach in single cell. Transient Receptor Potential (TRP) channels expression was determined by RT-PCR.
  
  
  RESULTS
  We showed that in MCD4 cells, short-term exposure to RGZ dramatically increases the amount of apically expressed AQP2 independently on cAMP production, PKA activation and AQP2 phosphorylation. RGZ elicited a cytosolic Ca(2+) transient due to Ca(2+) influx prevented by ruthenium red, suggesting the involvement of TRP plasma membrane channels. We identified TRPV6 as the possible candidate mediating this effect.
  
  
  CONCLUSIONS
  Taken together these results provide a possible molecular mechanism explaining the increased AQP2 membrane expression under RGZ treatment: in renal cells RGZ elicits Ca(2+) transients facilitating AQP2 exposure at the apical plasma membrane, thus increasing collecting duct water permeability. Importantly, this effect suggests an unexplored application of RGZ in the treatment of pathological states characterized by impaired AQP2 trafficking at the plasma membrane.
authors: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors: Giuseppe
authors: G
authors: Procino
authors: Andrea
authors: A
authors: Gerbino
authors: Serena
authors: S
authors: Milano
authors: Maria Celeste
authors: MC
authors: Nicoletti
authors: Lisa
authors: L
authors: Mastrofrancesco
authors: Monica
authors: M
authors: Carmosino
authors: Maria
authors: M
authors: Svelto
mesh_terms: D051399:Aquaporin 2 / Q000096:biosynthesis* / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics*; D000242:Cyclic AMP / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004705:Endocytosis / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects; D014667:Vasopressins / Q000378:metabolism
chemical_list: C496023:AQP2 protein, human; D051399:Aquaporin 2; D015220:Calcium Channels; D050916:TRPV Cation Channels; C422827:TRPV6 protein, human; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D014667:Vasopressins; D000242:Cyclic AMP