Rapamycin worsens renal function and intratubular cast formation in protein overload nephropathy.
Kidney Int
; 68(6): 2599-607, 2005 Dec.
Article
in En
| MEDLINE
| ID: mdl-16316336
ABSTRACT
BACKGROUND:
Rapamycin (sirolimus) is associated with functional nephrotoxicity in some patients with nephrotic glomerular diseases but the pathophysiologic mechanisms are not known. This study investigated the effects of rapamycin on renal function and structure in protein overload nephropathy.METHODS:
Rats with protein overload nephropathy [induced by bovine serum albumin (BSA), 2.1 g by daily intraperitoneal injection, day 0 to day 3] received daily intraperitoneal injections of either vehicle [dimethyl sulfoxide (DMSO)], rapamycin (0.2 mg/kg, an inhibitor of mammalian target of rapamycin), or roscovitine (3.5 mg/kg, a small molecule cyclin-dependent kinase inhibitor) (N= 9 each) from day -3 to day 3.RESULTS:
In protein overload nephropathy, rapamycin caused severe acute renal failure and mild hypercholesterolemia (both P < 0.05). Rapamycin dramatically increased intratubular cast formation, and proximal tubular epithelial cells were swollen and engorged with increased cytoplasmic protein droplets. The number of 5-bromo-2'-deoxyuridine (BrdU)-positive tubular epithelial cells increased by more than 20-fold on day 3 in protein overload nephropathy, and this was attenuated by 65% with rapamycin (P < 0.05), whereas roscovitine was ineffective. Rapamycin increased the protein expression of p27(kip1) in tubular epithelial cells, but did not alter D-type cyclin expression or apoptosis.CONCLUSION:
Rapamycin caused a specific pattern of acute renal injury characterized by increased intratubular cast formation in protein overload nephropathy. This could be due to disruption of a potentially important compensatory mechanism in nephrotic glomerular diseases involving tubular epithelial cell protein endocytosis and proliferation.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proteinuria
/
Sirolimus
/
Acute Kidney Injury
/
Immunosuppressive Agents
/
Kidney Tubules
Limits:
Animals
Language:
En
Journal:
Kidney Int
Year:
2005
Document type:
Article
Affiliation country:
Australia