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Open Access Research article

The role of phosphodiesterase 3 in endotoxin-induced acute kidney injury

Won-Il Choi123, Kun Young Kwon24, Jeong Wook Seo5, John Beagle3, Deborah A Quinn3 and Charles A Hales3*

Author Affiliations

1 Pulmonary Unit, Department of Internal Medicine, Dongsan Hospital, Keimyung University School of Medicine, Daegu, Korea

2 School of Medicine & Institute for Medical Genetics, Keimyung University, Daegu, Korea

3 Pulmonary/Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA

4 Department of Pathology, Dongsan Hospital, Keimyung University School of Medicine, Daegu, Korea

5 Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

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BMC Infectious Diseases 2009, 9:80  doi:10.1186/1471-2334-9-80

Published: 1 June 2009

Abstract

Background

Acute 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.

Methods

Animals 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.

Results

The 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.

Conclusion

These findings suggest a significant role for PDE3B as an important mediator of LPS-induced acute kidney injury.