Early treatment with everolimus exerts nephroprotective effect in rats with adriamycin-induced nephrotic syndrome.
BACKGROUND
Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria and excessive fluid retention. The effects of early versus late treatment with low or high doses of oral everolimus, a mammalian target of rapamycin inhibitor, on proteinuria in NS have not been previously described.


METHODS
The effects of early treatment (2 days prior to NS induction) versus late treatment (beginning 2 weeks following the establishment of NS) with a low (20 mg/L) or high (100 mg/L) dose of everolimus for 5-7 weeks on proteinuria and nephrin/podocin abundance were assessed in male adult SD rats with adriamycin-induced NS.


RESULTS
Adriamycin caused a significant increase in daily and cumulative proteinuria throughout the experimental period. Early, and to a lesser extent late treatment, with a low dose of everolimus, significantly decreased both daily and cumulative proteinuria and improved renal function. The anti-proteinuric effects of low-dose everolimus were associated with restoration of the disruptive glomerular nephrin/podocin abundance. In contrast, administration of a high dose of everolimus resulted in a decrease in proteinuria in NS rats, subsequently to deterioration of renal function.


CONCLUSIONS
Early, and to a lesser extent late treatment, with a low but not a high dose of everolimus is effective in reducing proteinuria in nephrotic rats. The mechanism may be via nephrin/podocin protection.
Department of Nephrology, Rambam Medical Center, Haifa, Israel.
Rawi
R
Ramadan
Diana
D
Faour
Hoda
H
Awad
Eleanor
E
Khateeb
Ravit
R
Cohen
Ali
A
Yahia
Rafael
R
Torgovicky
Raanan
R
Cohen
David
D
Lazari
Hiroshi
H
Kawachi
Zaid
Z
Abassi
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D019610:Cytoprotection / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D000068338:Everolimus; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; C486607:Kirrel1 protein, rat; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger; D004317:Doxorubicin; D000068338:Everolimus; D020123:Sirolimus