Decrease in kidney calbindin-D 28kDa as a possible mechanism mediating cyclosporine A- and FK-506-induced calciuria and tubular mineralization.
The use of the immunosuppressant cyclosporine A (CsA) is limited by its adverse renal effects. Most recently, we reported that the drug markedly decreases the levels of the calcium-binding protein calbindin-D 28kDa in kidneys of male Wistar rats. In the present study, the potential relationship between drug-induced nephrotoxicity and the decrease in kidney calbindin-D 28kDa was investigated. Four groups of male Wistar rats were treated for 10 or 31 days with either the immunosuppressant CsA (50 mg/kg/day), FK-506 (5 mg/kg/day), rapamycin (5 mg/kg/day) or with the nonimmunosuppressive cyclosporine derivative 3'keto-[Bmt1]-[Val2]-CsA (SDZ PSC-833) (50 mg/kg/day), and the effects on calcium homeostasis, kidney histology and renal calbindin-D 28kDa were examined. Similar effects were found with CsA and FK-506; both drugs strongly reduced kidney calbindin-D 28kDa protein levels, increased urine calcium excretion, caused intratubular calcification, and induced basophilic tubules. In contrast, rapamycin and SDZ PSC-833 caused no decrease in renal calbindin-D 28kDa levels, no noticeable alterations in calcium metabolism, and no renal calcification. The results provide evidence for a link between decreased renal calbindin, increased calcium urine excretion, and intratubular kidney calcification. The present data show no correlation between the decrease in renal calbindin and the induction of basophilic tubules; however, it needs to be investigated if these apparently independent kidney effects may have a common origin upstream of calbindin expression.
Aicher
L
L
Preclinical Safety, Toxicology SMU-881, Novartis Pharma Ltd., Basel, Switzerland.
Meier
G
G
Norcross
A J
AJ
Jakubowski
J
J
Varela
M C
MC
Cordier
A
A
Steiner
S
S
D000818:Animals; D064026:Calbindins; D002114:Calcinosis / Q000139:chemically induced*; D002118:Calcium / Q000652:urine*; D016572:Cyclosporine / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D011090:Polyenes / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D064030:S100 Calcium Binding Protein G / Q000032:analysis*; D020123:Sirolimus; D016559:Tacrolimus / Q000633:toxicity*
D064026:Calbindins; D007166:Immunosuppressive Agents; D011090:Polyenes; D064030:S100 Calcium Binding Protein G; D016572:Cyclosporine; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus