Sepsis-induced acute renal injury (AKI) occurs in 20%–50% of septic patients and nearly doubles the mortality of sepsis. Current therapy is mostly supportive and largely ineffective. The major obstacle to the development of new therapeutic approaches for sepsis-induced AKI is the lack of knowledge regarding the temporal relationships between the development of the inflammatory response, renal microvascular changes and end-organ injury. Pervious studies in our lab have shown renal microcirculatory dysfunction and oxidants generation during sepsis induced AKI. Hence, I hypothesized that peritubular capillary endothelial injury occurs early during sepsis and causes capillary hypoperfusion. Subsequently, the resulting hypoxic microenvironment favors the generation of oxidants and oxidant-mediated tubular cell injury, which contributes to renal failure.
The cecal ligation and puncture (CLP) model of sepsis was used to test this hypothesis in male 40-week C57BL mice. A detailed time-course study showed a rapid development of systemic hemodynamic dysfunction and renal microcirculatory failure that was closely followed by oxidants generation in the renal tubular epithelium. To examine the mechanism of renal capillary hypoperfusion, a sphingosine-1-phosphate (S1P) receptor agonist SEW2871 and antagonist JTE-013 were used to evaluate the role of capillary leakage in early microcirculatory dysfunction. The oxidant scavenger MnTMPyP was used to establish oxidant generation as the link between peritubular capillary hypoperfusion and renal tubular injury and actinonin, the meprin-A metalloproteinase inhibitor, was used to protect the tubular epithelium. Studies showed that a partial inhibition of capillary leakage did not prevent capillary hypoperfusion. However, scavenging oxidants or inhibiting meprin-A could actually reverse capillary hypoperfusion and, most importantly, delayed treatment improved renal function and in the case of MnTmPyP, prolonged survival. Together, my studies confirmed the notion that preventing tubular injury may actually allow capillary perfusion to recover by interrupting the cycle of injury between peritubular capillaries and the tubular epithelium.
In summary, this dissertation uncovered the pathophysiological processes leading to AKI during sepsis and evaluated new therapeutic targets. Results from these studies revealed that targeting oxidative stress and tubular injury could not only prevent renal injury but also allow recover of renal function even with delayed therapy.
|Advisor:||Mayeux, Philip R.|
|Commitee:||Gottschall, Paul E., MacMillan-Crow, Lee Ann, Post, Steven R., Telemaque, Sabine|
|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, Microcirculation, Oxidative stress, Sepsis, Tubular injury|
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