title: Delayed administration of pituitary adenylate cyclase-activating polypeptide 38 ameliorates renal ischemia/reperfusion injury in mice by modulating Toll-like receptors.
abstract: We investigated whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) ameliorates kidney injury after ischemia/reperfusion (IR) by modulating Toll-like receptor (TLR)-associated signaling pathways. Male C57BL/6 mice were subjected to bilateral renal ischemia for 45 min. PACAP38, 20 μg in 100 μl of saline, was administered i.p. at 24 and 48 h after IR, and mice were euthanized at 72h. In IR mice, PACAP38 maintained serum creatinine near control levels (0.81 ± 0.08 vs. 0.69 ± 0.17 mg/dl in controls, p=NS, vs. 1.8 ± 0.03 in saline-treated IR mice, p<0.01) and significantly reduced the expression of kidney injury biomarkers. PACAP38 significantly reduced the levels of apoptosis and neutrophil infiltration, and protected against tubular damage. With PCR arrays, 59 of 83 TLR-related genes significantly changed their expression after IR. TLR2 increased 162 fold, followed by Fas-associated death domain (37 fold) and TLR6 (24 fold), while ubiquitin-conjugating enzyme E2 variant 1 (UBE2V1) decreased 55 fold. PACAP38 given 24 and 48 h after IR injury significantly reversed these changes in 56 genes, including TLR2, TLR3, TLR4, TLR6, and genes in the NF-κB pathways. The alterations in TLR2, TLR3, TLR6, and UBE2V1 were confirmed by RT-PCR. After IR, PACAP38 also suppressed protein levels of TLR-associated cytokines. PACAP38 reversed the changes in IR-activated TLR-associated NF-κB signaling pathways even when treatment was delayed 24h. Therefore, PACAP38 could be an effective therapeutic for unexpected IR-mediated renal injury. The prominently IR-induced TLR-related genes identified in this study could be novel drug targets.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Tulane University, School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Altaf-M
authors.initials: AM
authors.lastname: Khan
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Solange
authors.initials: S
authors.lastname: Abdulnour-Nakhoul
authors.forename: Jerome L
authors.initials: JL
authors.lastname: Maderdrut
authors.forename: Eric E
authors.initials: EE
authors.lastname: Simon
authors.forename: Vecihi
authors.initials: V
authors.lastname: Batuman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051193:Toll-Like Receptors; D003404:Creatinine