title: Glutamine attenuates tubular cell apoptosis in acute kidney injury via inhibition of the c-Jun N-terminal kinase phosphorylation of 14-3-3.
abstract: OBJECTIVE
  Tubular cell apoptosis is linked to the development of acute kidney injury (AKI), which is a frequent complication of traumatic rhabdomyolysis. The 14-3-3 protein, a multifunctional regulatory protein, binds a variety of apoptotic proteins and is a target of c-Jun N-terminal kinase (JNK) in the cell death signaling pathway. Therefore, we examined whether JNK phosphorylates 14-3-3 and downstream mitochondrial death pathway mediates apoptosis in myoglobinuric acute kidney injury to determine whether these events are regulated by glutamine, which is known to induce heat shock protein 70 (Hsp70), or involved in the synthesis of glutathione (GSH).
  
  
  METHODS
  A prospective, randomized, controlled animal trial.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Male Sprague-Dawley rats.
  
  
  METHODS
  We utilized a rat model of myoglobinuric AKI. Glutamine or saline was administered intraperitoneally before and after glycerol injection. Apoptotic cell death was determined via transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and Hsp70, JNK, phospho-JNK, 14-3-3, phospho-14-3-3, and many other apoptotic proteins were examined via Western blot. Relative interactions between these proteins were tested by coimmunoprecipitation analyses. Also, GSH levels were determined to further test whether glutamine affects apoptotic cell death in myoglobinuric AKI.
  
  
  RESULTS
  Glutamine treatment elevated levels of Hsp70 or reduced GSH and attenuated tubular cell apoptosis in kidney tissues of rats with myoglobinuric AKI. Further, Hsp70 physically associated with JNK, thereby limiting its activation. In addition, JNK evidently interacted with 14-3-3, leading to its phosphorylation, Bad or Bax dissociation from 14-3-3, and subsequent Bax mitochondrial translocation and caspase activation in rats with acute renal failure. Glutamine treatment very modestly lowered elevated levels of serum creatinine in AKI rats.
  
  
  CONCLUSIONS
  A signaling link between JNK and 14-3-3 and subsequent mitochondrial death pathway may partly act as an early signaling that promotes apoptotic cell death leading to AKI, and glutamine may at least partially prevent apoptosis via enhancing Hsp70 or GSH levels.
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Gyeongsang National University, Jinju, Gyeongnam, South Korea.
authors.forename: Yoon Sook
authors.initials: YS
authors.lastname: Kim
authors.forename: Myeong Hee
authors.initials: MH
authors.lastname: Jung
authors.forename: Mee Young
authors.initials: MY
authors.lastname: Choi
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Vadim
authors.initials: V
authors.lastname: Sheverdin
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Ha
authors.forename: Dong Jun
authors.initials: DJ
authors.lastname: Park
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.forename: Wan Sung
authors.initials: WS
authors.lastname: Choi
authors.forename: Se-Ho
authors.initials: SH
authors.lastname: Chang
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000201:enzymology* / Q000209:etiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D005973:Glutamine / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D048948:14-3-3 Proteins; D005973:Glutamine; D048031:JNK Mitogen-Activated Protein Kinases