title: Albumin and glycated albumin activate KIM-1 release in tubular epithelial cells through distinct kinetics and mechanisms.
abstract: OBJECTIVE
  Kidney injury molecule-1 (KIM-1) serves as a useful marker for monitoring tubular injury, and sustained KIM-1 expression may be implicated in chronic kidney fibrosis. In this study, we examine the kinetics and mechanisms of KIM-1 release in human proximal tubular epithelial cells (PTEC) under the activation by major pathologic players in diabetic nephropathy, including human serum albumin (HSA), glycated albumin (AGE-BSA) and high glucose.
  
  
  METHODS
  The kinetics of KIM-1 release by PTEC under activation with HSA, AGE-BSA and high glucose, were determined by RT-PCR and ELISA. The activation profiles of major signaling pathways in PTEC were identified by PCR array. Based on the array data, blockade experiments were designed to assess their regulatory roles in KIM-1 release.
  
  
  RESULTS
  Prompt shedding of KIM-1 was observed in PTEC cultured for 4 h with HSA and AGE-BSA, but not with high glucose. Culturing PTEC for 3 days with AGE-BSA exhibited sustained up-regulation of KIM-1 release, but not with HSA. In all culture experiments, high glucose did not induce KIM-1 release in PTEC. HSA and AGE-BSA activated multiple signaling pathways in PTEC including NFκB, ERK1/2 and the oxidative stress pathways. Long-term culturing PTEC with AGE-BSA but not HSA activated the Jak-Stat pathway. While incubation of PTEC with diphenylene iodonium blocked the short-term release of KIM-1 mediated by HSA or AGE-BSA, Jak-Stat inhibitors diminished the long-term KIM-1 release by PTEC induced by AGE-BSA.
  
  
  CONCLUSIONS
  KIM-1 release in PTEC was differentially up-regulated by HSA and AGE-BSA. The short-term KIM-1 shedding was mediated by the reactive oxygen species, whereas Jak-Stat pathway regulates the long-term KIM-1 release.
authors: Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Room 301, Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China.
authors: Ai Ing
authors: AI
authors: Lim
authors: Loretta Y Y
authors: LY
authors: Chan
authors: Sydney C W
authors: SC
authors: Tang
authors: Kar Neng
authors: KN
authors: Lai
authors: Joseph C K
authors: JC
authors: Leung
mesh_terms: D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology; D007700:Kinetics; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D012709:Serum Albumin / Q000494:pharmacology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D017127:Glycation End Products, Advanced; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D011991:Receptors, Virus; D050791:STAT Transcription Factors; D012709:Serum Albumin; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D053612:Janus Kinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D005947:Glucose