Magnesium depletion enhances cisplatin-induced nephrotoxicity.
OBJECTIVE
Nephrotoxicity and magnesium (Mg)-depletion are well-known side effects to cisplatin (CP) treatment. The purpose of this present study was to investigate the role of Mg on CP induced changes in renal function. CP induced renal dysfunction was achieved by treatment with CP or vehicle (2.5 mg/kg) once weekly for 3 weeks. Since the CP-induced renal damage, including tubular reabsorption defects, is most prominent within the outer medulla (OM), changes in the expression pattern of OM aquaporins and sodium transporters including the Na,K-ATPase (alpha-subunit), type III Na,H-exchanger (NHE3), aquaporin 1 (AQP1) and 2 (AQP2) and the Na,K,2Cl-cotransporter (NKCC2) were investigated by semi-quantitative Western blotting.


METHODS
Rats had access to either a diet with standard Mg or to a Mg-depleted diet. Cisplatin was administered to female Wistar rats once a week for 3 weeks according to four regimens: (1) Cisplatin 2.5 mg/kg body weight i.p., to rats on a diet with standard Mg, (2) Cisplatin 2.5 mg/kg body weight i.p., to rats on a diet with low Mg, (3) Isotonic NaCl 2.5 ml/kg body weight i.p., to rats on a diet with standard Mg, (4) Isotonic NaCl 2.5 ml/kg body weight i.p., to rats on a diet with low Mg.


RESULTS
CP had no effect on plasma creatinine or urea in rats with standard Mg intake, but the expression of all five transporters was significantly reduced when compared to vehicle treated rats on standard Mg-intake. Vehicle treated rats on low Mg-intake had a significant reduction in the expression of Na,K-ATPase, NHE3 and NKCC2, but unchanged expression levels of AQP1 or AQP2 when compared to standard treated controls. Forty percent of the CP-treated rats on low Mg-intake died during the experiment and the remaining animals had marked increased plasma creatinine and urea. Furthermore, the Western blot analysis revealed an almost complete disappearance of all four transporters, suggesting a dramatic synergistic effect of CP and Mg-depletion on renal function including the expression pattern of outer medullary sodium transporters and aquaporins.


CONCLUSIONS
This study indicates a substantial additive effect of Mg-depletion on cisplatin induced renal toxicity as evidenced by significant changes in plasma creatinine and urea, renal failure induced mortality and loss of renal transporters. This should give cause for concern since the nephrotoxicity observed during cisplatin treatment might be substantiated by the known Mg-loss associated with cisplatin treatment especially in patients suffering from intense gastro-intestinal side effects.
Lajer
H
H
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark. lajer@dadlnet.dk
Kristensen
M
M
Hansen
H H
HH
Nielsen
S
S
Frøkiaer
J
J
Ostergaard
L F
LF
Christensen
S
S
Daugaard
G
G
Jonassen
T E N
TE
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D004032:Diet; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000517:prevention & control; D008274:Magnesium / Q000008:administration & dosage / Q000097:blood*; D011188:Potassium / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000097:blood; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D014508:Urea / Q000097:blood
D000970:Antineoplastic Agents; C578716:Slc12a1 protein, rat; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014508:Urea; D012964:Sodium; D003404:Creatinine; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium; D002945:Cisplatin; D011188:Potassium