The mTOR inhibitor everolimus attenuates the time course of chronic anti-Thy1 nephritis in the rat.
BACKGROUND
The antiproliferative immunosuppressant everolimus adversely affects the acute reversible anti-Thy1 nephritis model. We hypothesized that everolimus treatment started after the acute proliferative phase could even be beneficial in the chronic anti-Thy1 nephritis model in the rat.


METHODS
Chronic anti-Thy1 nephritis was induced by injection of the monoclonal antibody 1-22-3 in 20 male Sprague-Dawley rats 7 days after uninephrectomy. Two weeks after disease induction, rats were randomly treated with either everolimus or vehicle for 14 weeks. Changes in progression of renal disease were investigated by immunohistochemistry and real-time PCR 16 weeks after disease induction.


RESULTS
During chronic anti-Thy1 nephritis, the formation of focal segmental glomerulosclerosis lesions, the degree of interstitial fibrosis as well as the increase in proteinuria over 14 weeks was ameliorated by everolimus treatment. Increased glomerular hypertrophy observed in the vehicle-treated rats was completely prevented in the everolimus-treated nephritic rats. Increased glomerular fibronectin mRNA and protein as well as the renal influx of monocytes/macrophages was significantly reduced in the everolimus group. Everolimus reduced the pro-angiogenic factor vascular endothelial growth factor (VEGF) and VEGF mRNA in glomeruli, while the transforming growth factor-beta signaling pathway was not affected.


CONCLUSIONS
'Late' start of everolimus treatment demonstrates beneficial effects on the time course of chronic anti-Thy1 nephritis.
Wittmann
Sandra
S
Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany. sandra.wittmann@med4.imed.uni-erlangen.de
Daniel
Christoph
C
Braun
Andrea
A
Vogelbacher
Regina
R
Shimizu
Fuijo
F
Kawachi
Hiroshi
H
Hugo
Christian
C
D000818:Animals; D002908:Chronic Disease; D000068338:Everolimus; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D007518:Isoantibodies / Q000008:administration & dosage*; D008297:Male; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D007518:Isoantibodies; C035678:anti-Thy antibody; D000068338:Everolimus; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus