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Published on: June 23, 2015
Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease
Yunxia Tao1, Jun Kim, Robert W Schrier
1Division of Renal Diseases and Hypertension, University of ColoradoHealth Sciences Center, Denver, CO, USA.
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.
Insights
Rapamycin treatment significantly reduced kidney enlargement, cyst formation, and prevented renal failure in a polycystic kidney disease (PKD) rat model by decreasing tubular cell proliferation.
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Polycystic kidney disease (PKD) is characterized by increased tubular epithelial cell proliferation, leading to cyst formation and kidney dysfunction.
- Rapamycin, a known antiproliferative agent, has potential therapeutic applications in diseases driven by cell growth.
Purpose of the Study:
- To investigate the efficacy of rapamycin in mitigating tubular cell proliferation, cystogenesis, and renal failure in the Han:SPRD rat model of PKD.
Main Methods:
- Heterozygous (Cy/+) and control (+/+) rats were treated with rapamycin or vehicle for 5 weeks.
- Kidney size, cyst volume density, blood urea nitrogen (BUN) levels, and proliferating cell nuclear antigen (PCNA)-positive cells were assessed.
Main Results:
- Rapamycin treatment reduced kidney enlargement by 65% and cyst volume density by over 40% in Cy/+ rats.
- Rapamycin normalized elevated BUN levels and significantly decreased PCNA-positive cells in both cystic and non-cystic tubules.
- The drug markedly inhibited proliferation in cystic and non-cystic tubules, preventing kidney function loss.
Conclusions:
- Rapamycin effectively inhibits cell proliferation in polycystic kidney disease.
- Rapamycin treatment markedly reduces renal enlargement, cystogenesis, and prevents the decline in kidney function in a rat model of PKD.
