title: Effects of combined administration of rapamycin, tolvaptan, and AEZ-131 on the progression of polycystic disease in PCK rats.
abstract: Both experimental and clinical studies have suggested that any potential treatment of polycystic kidney disease (PKD) should start early and last for a long time to be effective, with unavoidable side reactions and considerable costs. The aim of the present study was to test how low doses of rapamycin (RAPA; 0.15 mg/kg ip for 4 days/wk), tolvaptan (TOLV; 0.005% in diet), or AEZ-131 (AEZ; a novel ERK inhibitor, 30 mg/kg for 3 days/wk by gavage), alone and in association, affect the progression of polycystic renal disease in PCK rats. Rats were treated for 8 wk starting at 4-6 wk of age. The efficacy of low doses of such drugs in inhibiting their respective targets was confirmed by immunoblot experiments. Compared with rats in the control (CON) group, RAPA treatment caused a significant reduction in cyst volume density (CVD; -19% vs. the CON group) and was numerically similar to that in TOLV-treated rats (-18%, not significiant), whereas AEZ treatment was not effective. RAPA + TOLV treatment resulted in a significantly lower CVD (-49% vs. the CON group) and was associated with a striking decrease in cAMP response element-binding protein phosphorylation, and similar data were detected in RAPA + AEZ-treated rats (-42%), whereas TOLV + AEZ treatment had virtually no effect. RAPA administration significantly lessened body weight gain, whereas TOLV administration resulted a mild increase in diuresis and a significant increase in cAMP urinary excretion. Histological data of tubular proliferation were in full agreement with CVD data. In conclusion, this study demonstrates that the association of low doses of RAPA, TOLV, and AEZ slows the progression of PKD with limited side effects, suggesting the use of combined therapies also in clinical trials.
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy; sabbatin@unina.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Sabbatini
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy;
authors.forename: Luigi
authors.initials: L
authors.lastname: Russo
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappellaio
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy; and.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Troncone
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy; and.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bellevicine
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: De Falco
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Naples, Italy.
authors.forename: Preziosa
authors.initials: P
authors.lastname: Buonocore
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy;
authors.forename: Eleonora
authors.initials: E
authors.lastname: Riccio
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bisesti
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Federico
authors.affiliation: Department of Public Health, University Federico II, Naples, Italy;
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077602:Tolvaptan; D016896:Treatment Outcome
chemical_list: D001552:Benzazepines; D004791:Enzyme Inhibitors; D000077602:Tolvaptan; D000242:Cyclic AMP; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: cyst volume density; extracellular signal-regulated kinase inhibitors; polycystic kidney disease; rapamycin; tolvaptan