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: Yunxia Tao, Jun Kim, Robert W Schrier, Charles L Edelstein
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 16 Issue 1 Pg. 46-51 (Jan 2005) ISSN: 1046-6673 [Print] United States
• PMID: 15563559 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Immunosuppressive Agents
• Sirolimus

Topics

• Animals
• Blood Urea Nitrogen
• Body Weight
• Cell Division (drug effects)
• Disease Progression
• Immunosuppressive Agents (pharmacology)
• Male
• Polycystic Kidney, Autosomal Dominant (drug therapy, pathology)
• Rats
• Rats, Mutant Strains
• Rats, Sprague-Dawley
• Renal Insufficiency (drug therapy, pathology, prevention & control)
• Sirolimus (pharmacology)