New insights into cyclosporine A nephrotoxicity by proteome analysis.
Using two-dimensional gel electrophoresis (2-DE), we recently discovered an association between decreased calcium-binding protein, calbindin-D 28 kDa, urinary calcium wasting and intratubular corticomedullary calcifications in rat kidney. This observation prompted us to investigate kidney tissues of other species, including man. In this paper we show that in dogs and monkeys, which are generally devoid of cyclosporine A (CsA)-mediated nephrotoxicity, renal calbindin levels were not affected by the CsA treatment whereas in CsA-treated human kidney-transplant recipients with renal vascular or tubular toxicity, a marked decrease in renal calbindin-D 28 kDa protein level was found in most of the kidney biopsy sections. The present results strongly suggest that calbindin is a marker for CsA-nephrotoxicity. The discovery of calbindin-D 28 kDa being involved in CsA toxicity has evolved from the application of 2-DE and has not been reported previously, proving that proteomics can provide essential information in mechanistic toxicology. Considering the current improvements in proteome methods it is expected that high throughput proteomics will become an indispensable tool in preclinical safety testing.
Aicher
L
L
Preclinical Safety, Novartis Pharma AG, Basel, Switzerland.
Wahl
D
D
Arce
A
A
Grenet
O
O
Steiner
S
S
D000818:Animals; D064026:Calbindins; D016572:Cyclosporine / Q000633:toxicity*; D004285:Dogs; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D064030:S100 Calcium Binding Protein G / Q000378:metabolism*
D064026:Calbindins; D007166:Immunosuppressive Agents; D064030:S100 Calcium Binding Protein G; D016572:Cyclosporine