title: Limb ischemic preconditioning protects against contrast-induced acute kidney injury in rats via phosphorylation of GSK-3β.
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.
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Nephrology, the Affiliated Changzhou No. 2 Hospital of Nanjing Medical College, Changzhou 213003, Jiangsu, China.
authors.forename: Tongqiang
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Kidney and Dialysis, Shanghai 200032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Kidney and Dialysis, Shanghai 200032, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yu
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53201, USA.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Liang
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Kidney and Dialysis, Shanghai 200032, China. Electronic address: ding.xiaoqiang@zs-hospital.sh.cn.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Ding
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003287:Contrast Media / Q000009:adverse effects*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D007472:Iohexol / Q000009:adverse effects*; D019194:Ischemic Preconditioning; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009392:Nephrectomy; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D003287:Contrast Media; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles; D007472:Iohexol; D008301:Maleimides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C495637:Nfe2l2 protein, rat; C417521:SB 216763; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605508:Gsk3b protein, rat
keywords: Acute kidney injury; Glycogen synthase kinase-3β; Iodinated contrast media; Limb ischemic preconditioning