GSK-3beta Inhibitor Induces Expression of Nrf2/TrxR2 Signaling Pathway to Protect against Renal Ischemia/Reperfusion Injury in Diabetic Rats

Kidney Blood Press Res. 2016;41(6):937-946. doi: 10.1159/000452598. Epub 2016 Dec 8.

Abstract

Background/aims: Diabetes mellitus (DM) can lead to renal damage and dysfunction, and exacerbate renal ischemia/reperfusion injury (RI/RI). The aim of this study was to investigate the protective effect of GSK-3β inhibitor TDZD-8 against RI/RI through Nrf2/TrxR2 signaling pathway in a rat DM model.

Methods: A DM rat model was established by a single injection of streptozocin. Diabetic rats were pretreated with TDZD-8 (1 mg/kg bw) or TDZD-8+auranofin (10 nmol/L, 5ml/kg bw), and then subjected to 45-min ischemia and 24-h reperfusion. Rats were equally randomized into four groups: a Sham-operated group, a RI/RI group, a TDZD-8 group, and a TDZD-8+auranofin group. Serum levels of BUN and Scr were measured. SOD activity, MDA content, and Nrf2, TrxR2 and caspase-3 expressions in rat kidney tissues were determined.

Results: Renal function was improved, oxidative stress and cell apoptosis were reduced, and the expression of Nrf2 and TrxR2 was up-regulated in TDZD-8 treated rats as compared with those in auranofin treated rats.

Conclusion: TDZD-8 may exert its protective effect against RI/RI by regulating the Nrf2/TrxR2 signaling pathway in the kidney tissue in DM.

MeSH terms

  • Animals
  • Auranofin / pharmacology
  • Diabetes Mellitus, Experimental
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • NF-E2-Related Factor 2 / drug effects
  • NF-E2-Related Factor 2 / metabolism
  • Rats
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / prevention & control*
  • Signal Transduction / drug effects*
  • Thiadiazoles / pharmacology*
  • Thioredoxin Reductase 2 / drug effects
  • Thioredoxin Reductase 2 / metabolism
  • Up-Regulation / drug effects

Substances

  • 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • Thiadiazoles
  • Auranofin
  • Thioredoxin Reductase 2
  • Glycogen Synthase Kinase 3 beta