Impact of reduced nephron mass on cyclosporine- and/or sirolimus-induced nephrotoxicity.
BACKGROUND
We evaluated the impact of reduced nephron mass on nephrotoxicity by cyclosporine A (CsA) and/or sirolimus (SRL).


METHODS
Renal function was tested in salt-depleted rats bearing two kidneys (2K), one kidney, or half a kidney (1/2K) and treated for 7 or 28 days with CsA (5 mg/kg) and/or SRL (0.8 mg/kg). We also measured the expression of aquaporin-2, sodium/phosphate cotransporter (NaPi)-2, paracellin-1, and kidney injury molecule (KIM)-1 by real-time polymerase chain reaction.


RESULTS
At 7 days in 2K, serum creatinine clearance (CrCl) was decreased only in CsA/SRL-treated group (P<0.05) compared with controls; in 1/2K, CrCl was decreased in all groups, but most dramatically in CsA/SRL group (P<0.05). Extended 28-day therapy worsened CrCl in all 1/2K groups (P<0.01). Although the expression of aquaporin-2, NaPi-2, and paracellin-1 mRNAs tended to increase in kidneys with a reduced nephron mass, NaPi-2 mRNA levels decreased in 1/2K rats exposed to CsA/SRL for 28 days (P<0.05). In contrast, low KIM-1 mRNA expression in control 2K rats increased fourfold in untreated 1/2K (P<0.05), and 50- to 200-fold in CsA/SRL-treated 1/2K (P=0.01).


CONCLUSIONS
Nephrotoxicity is significantly worsened by reduced nephron mass, which correlates with increased expression of KIM-1 and inhibited expression of NaPi-2.
Fernandes
Ida
I
Division of Immunology and Organ Transplantation, Department of Surgery, The University of Texas Medical School, Houston, TX, USA.
Zhang
Ye
Y
Qi
Yuhua
Y
Wang
Mo-Er
ME
Podder
Hemongshu
H
Lisik
Wojciech
W
Knight
Richard
R
Kahan
Barry D
BD
Stepkowski
Stanislaw M
SM
D000818:Animals; D051399:Aquaporin 2 / Q000096:biosynthesis / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D003404:Creatinine / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000633:toxicity*; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000633:toxicity; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D012307:Risk Factors; D020123:Sirolimus / Q000493:pharmacokinetics / Q000633:toxicity*; D050608:Sodium-Phosphate Cotransporter Proteins / Q000096:biosynthesis / Q000235:genetics
D051399:Aquaporin 2; D015815:Cell Adhesion Molecules; D003404:Creatinine; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D020123:Sirolimus; D050608:Sodium-Phosphate Cotransporter Proteins; C110936:Havcr1 protein, rat