Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease.
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.
Tao
Yunxia
Y
Division of Renal Diseases and Hypertension, University of ColoradoHealth Sciences Center, Denver, CO, USA.
Kim
Jun
J
Schrier
Robert W
RW
Edelstein
Charles L
CL
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*
D007166:Immunosuppressive Agents; D020123:Sirolimus