Sepsis is a serious medical condition that affects over 750,000 patients each year. Acute kidney injury (AKI) will develop in 20-50% of septic patients and more than doubles the mortality rate to above 70%. Therapeutic options are limited and fluid resuscitation and supportive care remain the foundation of treatment. Furthermore, the majority of septic patients present only after the onset of septic shock, when fluid resuscitation is less effective. Previous studies have shown that microcirculatory failure is correlated with reactive nitrogen species (RNS) generation in the renal tubules and it contributes to the development of AKI during sepsis. Resveratrol (3,5,4- trihydroxystilbene) is a polyphenol shown to reduce oxidative stress in various disease models. Hence, I hypothesized that resveratrol would directly scavenge the RNS, peroxynitrite, to protect the kidneys during sepsis.
To address this hypothesis I used both in vitro and in vivo approaches. First I demonstrated that resveratrol was a potent scavenger of peroxynitrite in vitro and was effective in protecting renal epithelial cells from the lethal effects of the peroxynitrite generator 5-amino 3-(4-morpholinyl)-1,2,3-oxadiazolium chloride (SIN-1). A detailed examined of the reaction products revealed the formation of nitrated resveratrol products suggesting resveratrol could provide functional protection by directly scavenging peroxynitrite.
For the in vitro studies I used the cecal ligation and puncture (CLP) murine model of sepsis-induced AKI. Resveratrol produced a dose-dependent protection of the renal microcirculation and renal function. Interestingly, resveratrol also improved renal blood flow and glomerular filtration rate without raising mean arterial pressure. Next, resveratrol was evaluated using a clinically relevant dosing regimen. When administered at 6 and 12 hours after CLP there was a significant improvement in the renal function and perhaps most importantly, improved 48-hour survival.
The final studies examined repair mechanisms conferred by resveratrol. Resveratrol was able to acutely increase SIRT1 activity, deacetylate p53, and increase mitochondrial capacity. All of these effects are consistent with promotion of epithelial cell recovery.
In summary, these preclinical studies showed that resveratrol could improve kidney function and survival during sepsis, possibly by protecting the renal microcirculation and scavenging RNS, even when administered after the onset of septic shock.
|Advisor:||Mayeux, Philiph R.|
|Commitee:||Hinson, Jack A., Radominska-Pandya, Anna, Rusch, Nancy J., Ryan, Michael J.|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 73/10(E), Dissertation Abstracts International|
|Keywords:||Acute kidney injury, Antioxidant, Peroxynitrite, Renal blood flow, Resveratrol, Sepsis|
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