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Influence of N-acetylcysteine on Klotho expression and its signaling pathway in experimental model of chronic cyclosporine nephropathy in mice.

Transplantation (2013-06-15)
Shang Guo Piao, Seok Hui Kang, Sun Woo Lim, Byung Ha Chung, Kyoung Chan Doh, Seong Beom Heo, Long Jin, Can Li, Chul Woo Yang
ABSTRACT

Cyclosporine A (CsA)-associated oxidative stress has been proposed as an important mechanism of renal injury. This study was designed to examine whether N-acetylcysteine (NAC), a well-known antioxidant, affects Klotho, antiaging gene, expression and its signaling pathway in an experimental model of chronic CsA nephropathy. Mice maintained on a low-sodium diet were given vehicle (olive oil, 1 mL/kg/day), CsA (30 mg/kg/day), NAC (150 mg/kg/day), or a combination of CsA and NAC for 4 weeks. The effect of NAC on CsA-induced renal injury was evaluated with basic parameters, histopathology, and markers of oxidative stress [8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion and manganese superoxide dismutase (MnSOD) expression]. The influence of NAC on Klotho and its signal pathway (p-AKT and p-FoxO1) in CsA-treated mouse kidney was evaluated with immunohistochemistry and/or immunoblot. Concomitant administration of CsA and NAC significantly improved renal function and attenuated tubulointerstitial fibrosis, and these changes were accompanied by decreased urinary 8-OHdG level and increased MnSOD expression. NAC treatment preserved Klotho gene expression compared with CsA treatment alone (P < 0.05), and this correlated with urinary 8-OHdG excretion (r = -0.934) and MnSOD expression (r = 0.873, P < 0.001 for both). Concomitant treatment of CsA and NAC translocated FoxO1 from the cytoplasm to the nucleus, implicating dephosphorylation of FoxO1 by NAC in p-AKT/p-FoxO1 pathway. NAC treatment preserves Klotho expression and modifies p-AKT/p-FoxO1 pathway in chronic CsA nephropathy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
N-Acetyl-L-cysteine, Sigma Grade, ≥99% (TLC), powder
Sigma-Aldrich
N-Acetyl-L-cysteine, BioXtra, ≥99% (TLC)
Sigma-Aldrich
N-Acetyl-L-cysteine, BioReagent, suitable for cell culture
Supelco
Cyclosporine, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
N-Acetyl-L-cysteine, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Cyclosporin A solution, 1.0 mg/mL in acetonitrile, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Cyclosporin A, VETRANAL®, analytical standard
Sigma-Aldrich
Cyclosporin A, from Tolypocladium inflatum, ≥95% (HPLC), solid
Sigma-Aldrich
Cyclosporin A, from Tolypocladium inflatum, BioReagent, for molecular biology, ≥95%
Sigma-Aldrich
Cyclosporin A, 97.0-101.5% (on dried basis)
Acetylcysteine, European Pharmacopoeia (EP) Reference Standard