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

Autor:	Pouranan veeraragoo, Honglei Yu, Renfa Huang, Qiao-Ling Zhou, Zhou Xiao
Rok vydání:	2011
Předmět:	Male Ischemia Renal function Apoptosis Pharmacology Kidney Kidney Function Tests Critical Care and Intensive Care Medicine Rats Sprague-Dawley chemistry.chemical_compound Basic Helix-Loop-Helix Transcription Factors In Situ Nick-End Labeling medicine Animals Receptor Notch2 bcl-2-Associated X Protein Homeodomain Proteins Inflammation Creatinine Renal ischemia business.industry NF-kappa B Interleukin Epithelial Cells Dipeptides General Medicine Acute Kidney Injury medicine.disease Rats medicine.anatomical_structure chemistry Nephrology Reperfusion Injury Immunology Cytokines Transcription Factor HES-1 Tumor necrosis factor alpha Amyloid Precursor Protein Secretases business Reperfusion injury Signal Transduction
Zdroj:	Renal Failure. 33:207-216
ISSN:	1525-6049 0886-022X
DOI:	10.3109/0886022x.2011.553979
Popis:	This study aims to investigate the role of Notch pathway in the renal ischemia/reperfusion injury (IRI)-associated inflammation and apoptosis.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.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.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.
Databáze:	OpenAIRE
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