Rapamycin worsens renal function and intratubular cast formation in protein overload nephropathy.
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.


CONCLUSIONS
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.
Coombes
Jason D
JD
Kidney Regeneration Laboratory, Centre for Transplant and Renal Research, The University of Sydney, Westmead Hospital, Sydney, Australia.
Mreich
Ellein
E
Liddle
Christopher
C
Rangan
Gopala K
GK
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003593:Cytoplasm / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007672:Kidney Cortex / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009000:Monocytes / Q000166:cytology; D011507:Proteinuria / Q000473:pathology / Q000503:physiopathology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077546:Roscovitine; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D020123:Sirolimus / Q000633:toxicity*
C534698:Ccnd3 protein, rat; C493962:Cdkn1b protein, rat; D056743:Cyclin D3; D016213:Cyclins; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D011687:Purines; D000077546:Roscovitine; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012710:Serum Albumin, Bovine; D020123:Sirolimus