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-rep erfusion damage in several organs. The neuropeptide pituitary adenylate cyc lase-activating polypeptide, PACAP-38, is a potent stimulus to enhance cell ular cAMP levels. This study tested the protective effect of enhancing endo genous cAMP levels by PACAP-38 in a model of warm renal ischemia. Methods. Sprague-Dawley rats underwent 40 min of bilateral warm renal ische mia. PACAP-38 continuous infusion began either before ischemia or at 6 hr o r 18 hr after ischemia. A mini-osmotic pump infused PACAP-38 throughout 7 d ays of follow-up. Groups were constructed with sham, ischemic control, and dibutyryl cAMP treated animals, and four PACAP-38 treatment groups, using 1 6 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 seru m creatinine levels on days 1, 2, 3, and 7 after ischemia. Conventional his tology was performed on day 7. Renal myeloperoxidase (MPO) activity, infilt rating CD45(+) cells, plasma and tissue cAMP, and serum IL-6 were measured. Results. Continuous administration of the high concentration of PACAP-38 am eliorated renal function and morphologic abnormalities induced by warm isch emia. Treatment with dibutyryl cAMP produced morphologic protection but onl y partial functional effect on the ischemic kidney. A 6-hour delay in the a dministration of the compound after ischemia offered similar protective eff ect, whereas an 18-hr delay did not. The neuropeptide clearly increased cir culating cAMP after ischemia but not cAMP in renal tissue. PACAP-38 increas ed circulating IL-6, and minimized renal inflammatory cell infiltration ind uced by ischemia-reperfusion injury, as evidenced by a reduction of MPO act ivity and the number of CD45(+) cells in ischemic renal tissue. Conclusions. Enhancement of endogenous circulating cAMP with PACAP-38 modul ates postischemic inflammatory response and strongly protects from ischemic acute renal failure, even when administration is delayed for 6 hr after in jury.