Delayed administration of pituitary adenylate cyclase-activating polypeptide 38 ameliorates renal ischemia/reperfusion injury in mice by modulating Toll-like receptors |
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Authors: | Altaf-M Khan Min Li Solange Abdulnour-Nakhoul Jerome L Maderdrut Eric E Simon Vecihi Batuman |
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Institution: | 1. Division of Nephrology and Hypertension, Department of Medicine, Tulane University, School of Medicine, New Orleans, LA 70112, USA;2. Division of Gastroenterology, Department of Medicine, Tulane University, School of Medicine, New Orleans, LA 70112, USA;3. Peptide Research Laboratory, Department of Medicine, Tulane University, School of Medicine, New Orleans, LA 70112, USA;4. Department of Pharmacology, Tulane University, School of Medicine, New Orleans, LA 70112, USA;5. Southeast Louisiana Veterans Health Care System, Department of Veterans Affairs, New Orleans, LA 70112, USA |
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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 72 h. 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 24 h. 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. |
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Keywords: | Aifm-1 apoptosis-inducing factor mitochondrion-associated-1 FADD Fas-associated death domain H& E hematoxylin and eosin IFN-γ interferon γ IL interleukin IR ischemia/reperfusion IRF interferon regulatory factor KIM-1 kidney injury molecule 1 MAPK mitogen-activated protein kinase MCP-1 monocyte chemotactic protein 1 (CCL2) NF-κB nuclear factor κB PACAP pituitary adenylate cyclase-activating polypeptide PAS periodic acid-Schiff TLR Toll-like receptor TNF-α tumor necrosis factor α TRIF Toll/interleukin 1 receptor domain-containing adapter inducing interferon-β TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling UBE2V1 ubiquitin-conjugating enzyme E2 variant 1 |
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