Activation of sensory neurons reduces ischemia/reperfusion-induced acute renal injury in rats.
BACKGROUND
Prostaglandin I2 (PGI2) produced by endothelial cells improves ischemia/reperfusion-induced acute renal injury by inhibiting leukocyte activation in rats. However, the underlying mechanism(s) of increased PGI2 production is not fully understood. Activation of sensory neurons increases endothelial PGI2 production by releasing calcitonin gene-related peptide (CGRP) in rats with hepatic ischemia or reperfusion. We examined here whether activation of sensory neurons increases PGI2 endothelial production, thereby reducing ischemia/reperfusion-induced acute renal injury.


METHODS
Anesthetized rats were subjected to 45 min of renal ischemia/reperfusion. Rats were pretreated with CGRP, capsazepine (a vanilloid receptor-1 antagonist), CGRP(8-37) (a CGRP receptor antagonist), or indomethacin (a cyclooxygenase inhibitor), or subjected to denervation of primary sensory nerves before ischemia/reperfusion.


RESULTS
Renal tissue levels of CGRP and 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2, increased after renal ischemia/reperfusion, peaking at 1 h after reperfusion. Overexpression of CGRP was also noted at 1 h after reperfusion. Increases in renal tissue levels of 6-keto-prostaglandin F1alpha at 1 h after reperfusion were significantly inhibited by pretreatment with capsazepine, CGRP(8-37), and indomethacin. Pretreatment with capsazepine, CGRP(8-37), indomethacin, and denervation of primary sensory nerves significantly increased blood urea nitrogen and serum creatinine levels, renal vascular permeability, renal tissue levels of myeloperoxidase activity, cytokine-induced neutrophil chemoattractant, and tumor necrosis factor-alpha, and decreased renal tissue blood flow. However, pretreatment with CGRP significantly improved these changes.


CONCLUSIONS
Our results suggest activation of sensory neurons in the pathologic process of ischemia/reperfusion-induced acute renal injury. Such activation reduces acute renal injury by attenuating inflammatory responses through enhanced endothelial PGI2 production.
Mizutani
Akio
A
Department of Anesthesiology and Critical Care Medicine, Oita University Faculty of Medicine, Yufu, Oita, Japan. mizutani@med.oita-u.ac.jp
Okajima
Kenji
K
Murakami
Kazunori
K
Mizutani
Sachiko
S
Kudo
Kyosuke
K
Uchino
Tetsuya
T
Kadoi
Yuji
Y
Noguchi
Takayuki
T
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis / Q000627:therapeutic use*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives / Q000627:therapeutic use; D018932:Chemokine CCL2 / Q000097:blood; D003714:Denervation; D007150:Immunohistochemistry; D007213:Indomethacin / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D010446:Peptide Fragments / Q000096:biosynthesis / Q000627:therapeutic use*; D009195:Peroxidase / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D018932:Chemokine CCL2; D010446:Peptide Fragments; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014409:Tumor Necrosis Factor-alpha; C058636:calcitonin gene-related peptide (8-37); D015121:6-Ketoprostaglandin F1 alpha; D009195:Peroxidase; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin; D007213:Indomethacin