The enhancement of endogenous cAMP with pituitary adenylate cyclase-activating polypeptide protects rat kidney against ischemia through the modulation of inflammatory response.
BACKGROUND
Cyclic nucleotide analogue administration improves ischemia-reperfusion damage in several organs. The neuropeptide pituitary adenylate cyclase-activating polypeptide, PACAP-38, is a potent stimulus to enhance cellular cAMP levels. This study tested the protective effect of enhancing endogenous cAMP levels by PACAP-38 in a model of warm renal ischemia.


METHODS
Sprague-Dawley rats underwent 40 min of bilateral warm renal ischemia. PACAP-38 continuous infusion began either before ischemia or at 6 hr or 18 hr after ischemia. A mini-osmotic pump infused PACAP-38 throughout 7 days of follow-up. Groups were constructed with sham, ischemic control, and dibutyryl cAMP treated animals, and four PACAP-38 treatment groups, using 16 pmol/hr or 160 pmol/hr of the compound, or delaying its administration by 6 hr or 18 hr after ischemia. Renal function was assessed by means of serum creatinine levels on days 1, 2, 3, and 7 after ischemia. Conventional histology was performed on day 7. Renal myeloperoxidase (MPO) activity, infiltrating CD45+ cells, plasma and tissue cAMP, and serum IL-6 were measured.


RESULTS
Continuous administration of the high concentration of PACAP-38 ameliorated renal function and morphologic abnormalities induced by warm ischemia. Treatment with dibutyryl cAMP produced morphologic protection but only partial functional effect on the ischemic kidney. A 6-hour delay in the administration of the compound after ischemia offered similar protective effect, whereas an 18-hr delay did not. The neuropeptide clearly increased circulating cAMP after ischemia but not cAMP in renal tissue. PACAP-38 increased circulating IL-6, and minimized renal inflammatory cell infiltration induced by ischemia-reperfusion injury, as evidenced by a reduction of MPO activity and the number of CD45+ cells in ischemic renal tissue.


CONCLUSIONS
Enhancement of endogenous circulating cAMP with PACAP-38 modulates postischemic inflammatory response and strongly protects from ischemic acute renal failure, even when administration is delayed for 6 hr after injury.
Riera
M
M
Department of Medicine, University of Barcelona, Ciutat Sanitària i Universitària de Bellvitge, L'Hospitalet de Llobregat, Spain.
Torras
J
J
Cruzado
J M
JM
Lloberas
N
N
Liron
J
J
Herrero
I
I
Navarro
M A
MA
Grinyo
J M
JM
D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D000242:Cyclic AMP / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000378:metabolism; D007511:Ischemia / Q000150:complications / Q000517:prevention & control*; D007668:Kidney / Q000378:metabolism; D008297:Male; D009393:Nephritis / Q000473:pathology*; D009479:Neuropeptides / Q000008:administration & dosage / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology*; D013997:Time Factors
C495403:Adcyap1 protein, rat; D015850:Interleukin-6; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D000242:Cyclic AMP