title: Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury.
abstract: Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1(+/-) rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1(+/-) rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1(+/-) rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.
authors.affiliation: Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.|Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Department of Urology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai, China.
authors.forename: Guangyuan
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Zeyuan
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Kristie
authors.initials: K
authors.lastname: Usa
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cowley
authors.affiliation: Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Niansong
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Liang
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000818:Animals; D000990:Antithrombin III / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020152:Antithrombin III Deficiency / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010641:Phenotype; D011460:Prostaglandins F / Q000378:metabolism; D055647:Rats, Transgenic; D015427:Reperfusion Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D012720:Severity of Illness Index; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D015415:Biomarkers; D011460:Prostaglandins F; C542513:SERPINC1 protein, human; D000990:Antithrombin III; D003404:Creatinine; C100006:prostaglandin F1