Faculty Collaboration Database

Limb ischemic preconditioning protects against contrast-induced acute kidney injury in rats via phosphorylation of GSK-3β. Free Radic Biol Med 2015 Apr;81:170-82

Date

12/03/2014

Pubmed ID

25451640

DOI

10.1016/j.freeradbiomed.2014.10.509

Scopus ID

2-s2.0-84924986258 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

Contrast-induced acute kidney injury (CI-AKI) resulting from the use of intravascular iodinated contrast media for diagnostic and interventional cardiovascular procedures is associated with substantial morbidity and mortality. Despite preventative measures intended to mitigate the risk of CI-AKI, there remains a need for a novel and effective therapeutic approach. Limb ischemic preconditioning (LIPC), where short-term ischemia/reperfusion is applied to an arm prior to administration of the contrast agent, has been shown in several trials to preserve renal function in patients at high risk for CI-AKI. However, the underlying mechanism by which this procedure provides renoprotection against contrast media insults is not known. Here, we explored the molecular mechanism(s) of LIPC-induced protection of the kidneys from CI-AKI, particularly the role of phosphorylated glycogen synthase kinase-3β (GSK-3β). We used a novel CI-AKI model consisting of 5/6 nephrectomized (NE) rats at 6 weeks after the ablative surgery. LIPC- or sham-treated rats were administered iohexol (10 ml/kg, 3.5 gI) via the tail vein. The results showed that LIPC protected the kidneys against iohexol-induced injury. This protective effect was accompanied by the attenuation of renal dysfunction, tubular damage, apoptosis, mitochondrial swelling, oxidative stress, and inflammation. Furthermore, LIPC-induced renoprotection was blocked via treatment with inhibitors of PI3K (wortmannin or LY294002), but not ERK (U0126 or PD98059). LIPC also increased the protein expression levels of phospho-Akt, phospho-GSK-3β, and nuclear Nrf2, and decreased the levels of nuclear NF-κB. A specific GSK-3β inhibitor (SB216763) mimicked this effect of LIPC, by inhibiting the opening of the mitochondrial permeability transition pore and reducing the levels of oxidative stress and inflammation via activation of Nrf2 and suppression of NF-κB. The above results demonstrate that LIPC induces protection against CI-AKI, making this procedure a promising strategy for preventing CI-AKI. In particular, this renoprotective effect involves the phosphorylation of GSK-3β.

Author List

Liu T, Fang Y, Liu S, Yu X, Zhang H, Liang M, Ding X

MESH terms used to index this publication - Major topics in bold

Acute Kidney Injury
Androstadienes
Animals
Apoptosis
Chromones
Contrast Media
Disease Models, Animal
Gene Expression Regulation
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Indoles
Iohexol
Ischemic Preconditioning
Kidney Tubules
Male
Maleimides
Mitochondrial Membrane Transport Proteins
Morpholines
NF-E2-Related Factor 2
NF-kappa B
Nephrectomy
Oxidative Stress
Phosphatidylinositol 3-Kinases
Phosphorylation
Proto-Oncogene Proteins c-akt
Rats
Rats, Sprague-Dawley