Notch2/Hes-1 Pathway Plays an Important Role in Renal Ischemia and Reperfusion Injury-Associated Inflammation and Apoptosis and the gamma-Secretase Inhibitor DAPT has a Nephroprotective Effect

This study aims to investigate the role of Notch pathway in the renal ischemia//reperfusion injury (IRI)-associated inflammation and apoptosis. Materials and 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 gamma gamma-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)-alpha alpha in serum samples and urinary N-acety-beta beta-D-glucosaminidase (NAG) were assayed. Histological examinations were performed. The protein expression of Notch2, hairy//enhancer of split 1 (hes-1), NF-kappa kappa B2, 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-alpha alpha, urinary NAG, Notch2, hes-1, NF-kappa kappa B2, 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-alpha alpha, 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-kappa kappa B2, 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. Conclusion: 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.