Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease.
The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal-specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore, we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 wk, followed by 7 wk without treatment, or continuously for 12 wk. Cessation of everolimus did not result in the appearance of renal cysts up to 7 wk postwithdrawal despite the reemergence of S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in striking noncystic renal parenchymal enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regimens ameliorated kidney function, preserved the glomerular-tubular connection, and reduced proteinuria. Pulse treatment at an early age delays cyst development but leads to striking glomerular and parenchymal hypertrophy. Our data might have an impact when long-term treatment using mTOR inhibitors in patients with autosomal dominant polycystic kidney disease is being considered.
Zurich Center for Integrative Human Physiology (ZIHP), Zürich, Switzerland.
Ming
M
Wu
Alexandre
A
Arcaro
Zsuzsanna
Z
Varga
Alexander
A
Vogetseder
Michel
M
Le Hir
Rudolf P
RP
Wüthrich
Andreas L
AL
Serra
D000284:Administration, Oral; D000818:Animals; D004334:Drug Administration Schedule; D004655:Emulsions; D000068338:Everolimus; D006984:Hypertrophy; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011494:Protein Kinases / Q000187:drug effects*; D011507:Proteinuria / Q000188:drug therapy; D020551:Pulse Therapy, Drug; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases
D004655:Emulsions; D007166:Immunosuppressive Agents; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus