title: Notch2/Hes-1 pathway plays an important role in renal ischemia and reperfusion injury-associated inflammation and apoptosis and the γ-secretase inhibitor DAPT has a nephroprotective effect.
abstract: This study aims to investigate the role of Notch pathway in the renal ischemia/reperfusion injury (IRI)-associated inflammation and apoptosis.
  
  
  METHODS
  Male Sprague-Dawley rats were divided into three groups: normal saline (NS)-treated sham rats, NS-treated ischemia/reperfusion (I/R) rats, and N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) (a γ-secretase inhibitor) treated I/R rats. I/R rat model underwent nephrectomy of the right kidney and was subjected to 60 min of left renal pedicle occlusion followed by 24 h, 48 h, and 72 h of reperfusion, respectively. The levels of creatinine, urea nitrogen (BUN), interleukin (IL)-6, tumor necrosis factor (TNF)-α in serum samples and urinary N-acety-β-d-glucosaminidase (NAG) were assayed. Histological examinations were performed. The protein expression of Notch2, hairy/enhancer of split 1 (hes-1), NF-κB2, monocyte chemoattractant protein (MCP)-1, B-cell lymphoma 2 (bcl-2), and bcl-2-associated X (bax) were detected and the degree of apoptosis of tubular cells was evaluated.
  
  
  RESULTS
  Renal IR induced severe tubular damage, caused significant increases in the Scr, BUN, IL-6, TNF-α, urinary NAG, Notch2, hes-1, NF-κB2, MCP-1, ratio of tubule cells apoptosis, and reduction in the ratio of bcl-2 to bax. However, DAPT treatment significantly reduced the level of Scr, BUN, IL-6, TNF-α, and NAG. Thus, I/R activates Notch2/hes-1 signaling and DAPT treatment can ameliorate the severity of tubular damage after renal IRI, lower the expression of NF-κB2, MCP-1, and bax protein, increase the expression of bcl-2 protein, and reduce the ratio of terminal 2-deoxyuridine 5-triphosphate nick end-labeling-positive cells.
  
  
  CONCLUSIONS
  Notch signaling plays an important role in the renal IRI-associated inflammation and apoptosis. DAPT can protect against IRI through partly suppressing inflammation and apoptosis, which could constitute a new target for AKI.
authors.affiliation: Department of Nephrology, Xiangya Hospital of Central South University, Changsha, PR China.
authors.forename: RenFa
authors.initials: R
authors.lastname: Huang
authors.forename: QiaoLing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Pouranan
authors.initials: P
authors.lastname: Veeraragoo
authors.forename: HongLei
authors.initials: H
authors.lastname: Yu
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D004847:Epithelial Cells / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051883:Receptor, Notch2 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D004151:Dipeptides; D018398:Homeodomain Proteins; D016328:NF-kappa B; D051883:Receptor, Notch2; D000072056:Transcription Factor HES-1; D051028:bcl-2-Associated X Protein; C489735:Hes1 protein, rat; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497766:Notch2 protein, rat