Cyclosporine increases renal parathyroid hormone-related protein expression in vivo in the rat.
BACKGROUND
Clinical use of cyclosporine (CsA) is limited by its known nephrotoxicity. Parathyroid hormone (PTH)-related protein (PTHrP) increases after acute renal ischemia and stimulates proliferation of renal cells in culture. Herein, we have examined whether the renal expression of PTHrP and its PTH/PTHrP receptor is affected by chronic CsA nephrotoxicity.


METHODS
Rats were randomly assigned to receive daily intramuscular injections of either CsA (25 mg/kg) or the same volume of the vehicle olive oil (control) for 3 weeks. At this time interval, under ether anesthesia, rat blood and kidneys were obtained for analytical determinations, and total RNA isolation or immunohistochemistry, respectively.


RESULTS
Serum urea was 11+/-2 and 6+/-1 mmol/L (P < 0.01) in CsA-treated and control rats, respectively. We found that PTH/PTHrP receptor mRNA was unchanged, but PTHrP mRNA, and also transforming growth factor-beta1 mRNA expression as positive control, was about twofold increased in the kidney of CsA-treated rats. This was accompanied by increased PTHrP immunostaining in renal cortical tubules, associated with tubule vacuolation.


CONCLUSIONS
This study demonstrates an up-regulation of PTHrP, associated with chronic CsA-induced nephrotoxicity. Our findings support a role for PTHrP in the CsA-injured kidney.
Garcia-Ocaña
A
A
Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain.
Gomez-Casero
E
E
Peñaranda
C
C
Sarasa
J L
JL
Esbrit
P
P
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D016212:Transforming Growth Factor beta; D016572:Cyclosporine