Pituitary adenylate cyclase-activating polypeptide prevents cisplatin-induced renal failure.
Cisplatin is widely used for cancer chemotherapy, but nephrotoxicity is a major dose-limiting side effect. Our recent studies in vitro have shown that pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorated cisplatin nephrotoxicity and that the renoprotection with PACAP38 was mediated by the PAC(1) receptor and through the p53-dependent and -independent suppression of apoptosis of human renal proximal tubular epithelial cells. In the present studies, PACAP38 prevented the rise in blood urea nitrogen and serum creatinine in mice treated with cisplatin. Cisplatin-exposed mice treated with PACAP38 had relatively well-preserved tubular integrity, even when the treatment started 24 h after cisplatin exposure. PACAP38 also reduced plasma and kidney levels of tumor necrosis factor-α and restored collagen IV levels. The damage to mouse kidney tubules caused by cisplatin involved p53 accumulation and was partially reversed by treatment with PACAP38. PACAP38 ameliorates cisplatin-induced acute kidney injury even when treatment started 24 h after the onset of injury and increases tubular regeneration, which further facilitates restoration of kidney function in addition to its anti-apoptotic effects.
Li
Min
M
Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-45, 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
D000818:Animals; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D005109:Extracellular Matrix / Q000737:chemistry; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
D050814:Octamer Transcription Factor-3; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; D002945:Cisplatin