Abstract
BackgroundAcute kidney injury frequently accompanies sepsis. Endotoxin is known to reduce tissue levels of cAMP and low levels of cAMP have been associated with renal injury. We, therefore, hypothesized that endotoxin induced renal injury by activating phosphodiesterase 3 (PDE3) which metabolizes cAMP and that amrinone an inhibitor of PDE3 would prevent the renal injury.MethodsAnimals were divided into three groups (n = 7/group): 1) Control (0.9% NaCl infusion without LPS); 2) LPS (0.9% NaCl infusion with LPS); 3) Amrinone+LPS (Amrinone infusion with LPS). Either lipopolysaccharide (LPS) or vehicle was injected via the jugular vein and the rats followed for 3 hours. We explored the expression of PDE3 isoenzymes and the concentrations of cAMP in the tissue.ResultsThe PDE3B gene but not PDE3A was upregulated in the kidney of LPS group. Immunohistochemistry also showed that PDE3B was expressed in the distal tubule in the controls and LPS caused PDE3B expression in the proximal as well. However, PDE3A was not expressed in the kidney either in the control or LPS treated groups. Tissue level of cAMP was decreased after LPS and was associated with an increase in blood urea nitrogen, creatinine, ultrastructural proximal tubular changes, and expression of inducible nitric oxide synthase (iNOS) in the endotoxemic kidney. In septic animals the phosphodiesterase 3 inhibitor, amrinone, preserved the tissue cAMP level, renal structural changes, and attenuated the increased blood urea nitrogen, creatinine, and iNOS expression in the kidney.ConclusionThese findings suggest a significant role for PDE3B as an important mediator of LPS-induced acute kidney injury.
Highlights
In the amrinone+LPS group, mean arterial pressure (MAP) was mildly but significantly lower 30 min after starting of amrinone infusion compared with the two other groups
In the amrinone+LPS group, MAP remained above 80 mm Hg throughout the experiment, while the other 2 groups MAP stayed above 85 mm Hg
LPS caused a decrease in renal tissue cAMP that was associated with an increased expression of PDE3B, but not PDE3A
Summary
Endotoxin is known to reduce tissue levels of cAMP and low levels of cAMP have been associated with renal injury. We hypothesized that endotoxin induced renal injury by activating phosphodiesterase 3 (PDE3) which metabolizes cAMP and that amrinone an inhibitor of PDE3 would prevent the renal injury. Acute renal failure (ARF) frequently occurs in the systemic inflammatory response syndrome. An increase in cellular cAMP protects hypoxemic induced endothelial injury by preserving its barrier function [5], and improves post-ischemic recovery in the liver and kidney [6,7]. Tissue Cyclic-3',5'-adenosine monophosphate (cAMP) levels are determined by the balance between activities of the synthesizing enzyme and the catabolizing enzymes, such as the cyclic 3',5'-nucleotide phosphodiesterases (PDE) that hydrolyze the 3'-phosphoester bond of cAMP to its biologically inactive noncyclic nucleotides 5'-AMP [8]. The PDE3B gene has been shown to be present in the urogenito-epithelium [10]
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