title: Down-regulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress-induced podocyte apoptosis plays a critical role in the development of diabetic nephropathy (DN). Here, we tested the hypothesis that suppression of PERK-ATF4-CHOP pathway by Astragaloside IV (AS-IV) is associated with inhibition of ER stress-induced podocyte apoptosis in streptozotocin (STZ)-induced diabetic rats.
  
  
  METHODS
  Diabetic rats were treated with AS-IV at 5 and 10 mg·kg-1·d-1, p.o., for 12 weeks. Albuminuria examination, hematoxylin & eosin staining and TUNEL analysis were performed. Immunohistochemistry, western blot, and real-time PCR were used to detect renal expression of ER chaperone GRP78 and ER-associated apoptosis proteins.
  
  
  RESULTS
  Treatment with AS-IV ameliorated albuminuria and renal histopathology in diabetic rats. Diabetic rats had significant increment in podocyte apoptosis as well as phosphorylated PERK and eIF2α in the kidneys, which were attenuated by AS-IV treatment. Furthermore, diabetic rats were found to have increased protein and mRNA expressions of GRP78 and ER-associated apoptosis proteins, such as ATF4, CHOP and TRB3, which were also attenuated by AS-IV treatment. Increased Bax expression and decreased Bcl-2 expression were detected in diabetic rats, and these changes were partially restored by AS-IV treatment.
  
  
  CONCLUSIONS
  The protective effect of AS-IV on ER stress-induced podocyte apoptosis is associated with inhibition of PERK-ATF4-CHOP pathway. Down-regulation of PERK- ATF4-CHOP pathway by AS-IV may be a novel strategy for the treatment of DN.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Chen
authors.forename: Dingkun
authors.initials: D
authors.lastname: Gui
authors.forename: Jianguo
authors.initials: J
authors.lastname: Chen
authors.forename: Dongyuan
authors.initials: D
authors.lastname: He
authors.forename: Yunling
authors.initials: Y
authors.lastname: Luo
authors.forename: Niansong
authors.initials: N
authors.lastname: Wang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051701:Activating Transcription Factor 4; D005947:Glucose; D006360:Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012503:Saponins; D051742:Transcription Factor CHOP; D014315:Triterpenes; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C052064:astragaloside A