Pituitary adenylate cyclase-activating polypeptide ameliorates cisplatin-induced acute kidney injury.
Cisplatin nephrotoxicity involves DNA damage, proinflammatory responses and apoptosis/necrosis of renal proximal tubular epithelial cells. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to protect kidneys from ischemic injury and light chain-induced damage by modulating inflammation. Confluent monolayer of HK-2 human renal cells were exposed to 50 microM cisplatin in the presence or absence of either PACAP38 or p53 siRNA. Mice injected with cisplatin were also treated with PACAP38 daily for 3 days. The damage to HK-2 cells caused by cisplatin involved the activation of p53, caspase-7, and poly (ADP-ribose) polymerase-1 (PARP-1). PACAP38 prevented the decrease in the apurinic/apyrimidinic endonuclease-1 by suppressing p53 activation and blocked the cleavage of caspase-7 and PARP-1 in cisplatin-exposed cells. PACAP also markedly inhibited cisplatin-induced apoptotic tubule cell death. Exposure to cisplatin significantly suppressed the expression of fibronectin and collagens I and IV, and altered the integrin repertoire of human renal tubule cells, while PACAP partially reversed the reduction of fibronectin, collagen IV, and the integrin subunits in cells exposed to cisplatin. Experiments with PACAP receptor antagonists and siRNA silencing of p53 showed that the renoprotection with PACAP was mediated by the PAC(1) receptor and through both p53-dependent and -independent suppression of apoptosis. PACAP was renoprotective in vivo and prevented the rise in blood urea nitrogen and creatinine in mice treated with cisplatin. These results suggest that p53 plays a pivotal role in decreased integrin-mediated extracellular matrix component expression in cisplatin-induced tubule cell apoptosis, and reveal a novel aspect of PACAP-mediated renoprotection.
Li
Min
M
Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA. minlee@tulane.edu
Balamuthusamy
Saravanan
S
Khan
Altaf M
AM
Maderdrut
Jerome L
JL
Simon
Eric E
EE
Batuman
Vecihi
V
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D016023:Integrins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D034741:RNA, Small Interfering; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin