Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury. Kidney Int 2015 Oct;88(4):796-803
Date
06/25/2015Pubmed ID
26108065Pubmed Central ID
PMC4589441DOI
10.1038/ki.2015.176Scopus ID
2-s2.0-84942983545 (requires institutional sign-in at Scopus site) 61 CitationsAbstract
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.
Author List
Wang F, Zhang G, Lu Z, Geurts AM, Usa K, Jacob HJ, Cowley AW, Wang N, Liang MAuthor
Aron Geurts PhD Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acute Kidney InjuryAged
Animals
Antithrombin III
Antithrombin III Deficiency
Apoptosis
Biomarkers
Cardiac Surgical Procedures
Creatinine
Disease Models, Animal
Female
Gene Knockdown Techniques
Genetic Predisposition to Disease
Heterozygote
Humans
Kidney
Macrophages
Male
Middle Aged
Oxidative Stress
Phenotype
Prostaglandins F
Rats, Transgenic
Reperfusion Injury
Risk Factors
Severity of Illness Index
Signal Transduction
Time Factors