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


CONCLUSIONS
These findings suggest a significant role for PDE3B as an important mediator of LPS-induced acute kidney injury.
Choi
Won-Il
WI
Pulmonary Unit, Department of Internal Medicine, Dongsan Hospital, Keimyung University School of Medicine, Daegu, Korea. wichoi@dsmc.or.kr
Kwon
Kun Young
KY
Seo
Jeong Wook
JW
Beagle
John
J
Quinn
Deborah A
DA
Hales
Charles A
CA
D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000648:ultrastructure; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats
D008070:Lipopolysaccharides; D003404:Creatinine; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517290:Pde3a protein, rat; C517294:Pde3b protein, rat; D000676:Amrinone