title: Cannabinoid receptor 2 expression in human proximal tubule cells is regulated by albumin independent of ERK1/2 signaling.
abstract: BACKGROUND
  The cannabinoid receptor type 2 (CB2) is reduced in podocytes of animals and humans with Type 2 Diabetes Mellitus (T2DM), with activation of CB2 ameliorating albuminuria in animals. As albuminuria also is due to proximal tubule dysfunction, the aim of this study is to investigate tubular expression of CB2 under diabetic conditions in addition to the cell signaling pathways that underlie these changes.
  
  
  METHODS
  We characterized total CB2 protein in diabetic animals and in Human Kidney 2 (HK2) cells exposed to elevated albumin and glucose, the levels of CB2 mRNA and protein. We also used latrunculin to determine if internalization of albumin was required to regulate CB2 levels. Finally, we characterized the levels of active and total AKT, ERK1/2 and p38 in response to albumin.
  
  
  RESULTS
  There were no changes to CB2 expression in kidney lysate from diabetic rats. In HK2 cells, expression of CB2 was unaltered following exposure to high glucose. High albumin treatment alone and in combination with high glucose, resulted in a significant reduction in CB2 receptor mRNA expression at 6 and 18 hours. CB2 protein expression was reduced at 6 and 24 hours, in high albumin and in combination with high glucose. Internalization of albumin was required to regulate CB2 levels, and inhibition of ERK1/2, did not rescue the loss of CB2 in response to albumin.
  
  
  CONCLUSIONS
  We have demonstrated that internalization of albumin is required to reduce CB2 mRNA and protein expression in proximal tubules in vitro. Consequently, altered expression of CB2 in both the podocytes and tubules may contribute to the albuminuria observed in T2DM.
authors.affiliation: Biomedical and Lifestyle Diseases Unit, Victoria University, College of Biomedical and Health Sciences, The University of Melbourne, Melbourne, Australia.
authors.forename: Kayte A
authors.initials: KA
authors.lastname: Jenkin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McAinch
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Briffa
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.forename: Philip
authors.initials: P
authors.lastname: Poronnik
authors.forename: Deanne H
authors.initials: DH
authors.lastname: Hryciw
mesh_terms: D000418:Albumins / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D050199:Podocytes / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000418:Albumins; C469526:Cnr2 protein, rat; D043885:Receptor, Cannabinoid, CB2; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose