title: Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease.
abstract: Increased tubular epithelial cell proliferation is a prerequisite for cyst formation and expansion in polycystic kidney disease (PKD). Rapamycin is a potent antiproliferative agent. The aim of the present study was to determine the effect of rapamycin on tubular cell proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 wk of age and then treated with rapamycin 0.2 mg/kg per d intraperitoneally or vehicle (ethanol) for 5 wk. Vehicle-treated Cy/+ rats had a more than doubling of kidney size compared with +/+ rats. Rapamycin reduced the kidney enlargement by 65%. Rapamycin significantly reduced the cyst volume density in Cy/+ rats by >40%. Blood urea nitrogen was 59% increased in vehicle-treated Cy/+ rats compared with +/+ rats. Rapamycin reduced the blood urea nitrogen to normal in Cy/+ rats. The number of proliferating cell nuclear antigen (PCNA)-positive cells per noncystic tubule was eightfold increased in vehicle-treated Cy/+ compared with +/+ rats. Rapamycin significantly reduced the number of PCNA-positive cells in noncystic tubules of Cy/+ rats. In addition, the number of PCNA-positive cells per cyst in Cy/+ rats was significantly reduced by rapamycin. In summary, in a rat model of PKD, rapamycin treatment (1) decreases proliferation in cystic and noncystic tubules, (2) markedly inhibits renal enlargement and cystogenesis, and (3) prevents the loss of kidney function.
authors.affiliation: Division of Renal Diseases and Hypertension, University of ColoradoHealth Sciences Center, Denver, CO, USA.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Tao
authors.forename: Jun
authors.initials: J
authors.lastname: Kim
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight; D002455:Cell Division / Q000187:drug effects; D018450:Disease Progression; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000473:pathology*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus