Protective action of ulinastatin against cisplatin nephrotoxicity in mice and its effect on the lysosomal fragility.
The development of azotemia after cisplatin injection in mice was inhibited by ulinastatin treatment in a dose-dependent manner. Reduction in creatinine clearance and elevation in fractional excretion of sodium in mice receiving cisplatin was ameliorated by ulinastatin administration. Epithelial necrosis and hyaline cast formation in the proximal tubule were also suppressed. Ulinastatin showed no influence on the kidney platinum level after cisplatin injection. In LLC-PK1 cells, addition of ulinastatin to the incubation medium markedly reduced the release of N-acetyl-beta-D-glucosaminidase, on of the lysosomal enzymes, during hypotonic treatment only when cells were damaged with cisplatin. On the other hand, ulinastatin showed no effect on the elevation of malondialdehyde concentration in the murine kidney cortical slices after the treatment with cisplatin. These results indicate that ulinastatin has a protective effect against cisplatin nephrotoxicity, and its prevention of the increase in lysosomal fragility is a probable mechanism involved in the renal protection.
Yamasaki
F
F
Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd, Shizuoka, Japan.
Ishibashi
M
M
Nakakuki
M
M
Watanabe
M
M
Shinkawa
T
T
Mizota
M
M
D000818:Animals; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects; D007672:Kidney Cortex / Q000737:chemistry / Q000187:drug effects; D007677:Kidney Function Tests; D018374:LLC-PK1 Cells / Q000187:drug effects / Q000648:ultrastructure; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009961:Orosomucoid / Q000378:metabolism; D009995:Osmosis; D010984:Platinum / Q000032:analysis; D013552:Swine; D014361:Trypsin Inhibitors / Q000494:pharmacology*; D014511:Uremia / Q000139:chemically induced / Q000188:drug therapy*
D006023:Glycoproteins; D009961:Orosomucoid; D014361:Trypsin Inhibitors; D010984:Platinum; D008315:Malondialdehyde; D003404:Creatinine; D005978:Glutathione; C028665:urinastatin; D002945:Cisplatin