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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 The heterozygous Han:SPRD rat exhibits many of the features of ADPKD in humans, including (1) autosomal dominant inheritance; (2) relatively slow progression to end-stage renal failure with uremia, hypertension, and anemia; (3) bilateral renal involvement; (4) increased proliferation of renal cyst cells; and (5) more aggressive disease in males (2). The Han:SPRD rat is a suitable and well-documented animal model of PKD even though the defect is based on a mutation of a gene locus that is not a homologue of either the PKD1 or the PKD2 locus (3-6).Human and experimental data provide strong evidence that abnormal proliferation in tubular epithelial cells plays a crucial role in cyst development and/or growth in PKD (7). Genetic manipulations that induce the proliferation of tubular epithelial cells in mice cause cysts to form in the kidney (8,9). Rapamycin is a Food and Drug Administration-approved immunosuppressive and powerful antiproliferative drug (10). In view of the importance of tubular cell proliferation in cyst formation and the antiproliferative effects of rapamycin, we developed the hypothesis that rapamycin would reduce cyst formation and disease progression in PKD via inhibition of tubular cell proliferation. Materials and Methods AnimalsThe study was conducted in heterozygous (Cy/ϩ) and normal littermate control (ϩ/ϩ) Han:SPRD rats. All of the normal rats and Cy/ϩ rats studied were male. The Cy/ϩ Han:SPRD rat develops clinically detectable PKD by 8 wk of age as evidenced by a doubling of kidney size and kidney failure compared with ϩ/ϩ control rats (2,4). A colony of Han:SPRD rats was established in our animal care facility from a litter that was obtained from the Polycystic Kidney Program at the University of Kansas Medical Center. The study protocol was approved by the University of Colorado Health Sciences Center Animal Care and Use Committee. Rats had free access to tap water and standard rat diet. Experimental ProtocolMale Cy/ϩ and ϩ/ϩ 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. Rapamycin was obtained from LC Laboratories (Woburn, MA), and a 1 mg/ml stock solution in 100% ethan...

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