The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common renal genetic disease in humans with an estimated incidence of 1:400-1000. Cyst expansion progresses slowly, and renal function is typically not compromised until the fifth decade but then the decline to renal failure is precipitous usually occurring in 5-10 years in 50% of patients. There are currently no drugs approved for the treatment of ADPKD. Based on our previous observations that PPARγ agonists inhibit CFTR synthesis and that pioglitazone feeding ameliorates PKD progression in the PCK rat model, we have hypothesized that the PPARγ agonists, pioglitazone (pio) and rosiglitazone (rosi), could be used to treat ADPKD. CFTR is the Cl- channel in the epithelial cells lining the cysts that is responsible for Cl- driven fluid secretion into the cyst lumen causing cyst expansion. Both pio and rosi are insulin sensitizing agents which have been used to treat diabetic patients for many years, albeit with some dose related side effects. We have fed the PCK rat (a slowly progressing PKD model) with super-pharmacological (4.0 mg/kg BW; high dose) and sub-pharmacological (0.04 mg/kg BW; low dose) rosi from week 4 to 28. An alternative, rapidly progressing model of renal cystic disease, the WPK/WPK rats, were fed with high (20.0 mg/kg BW) and low (0.2 mg/kg BW) doses of pio from day 5 to 18. At the end of the appropriate time period, the animals were euthanized with an overdose (i.p.) of sodium pentobarbital. The kidneys were weighed and then prepared for histological sections which were used to determine various parameters including cyst volume. In the PCK rats both super- and sub-pharmacological concentrations of rosi resulted in statistically significant (ANOVA one way, P less than 0.05) decreases in kidney weight and renal cyst volume. The average (+- S.E.M.) kidney weights of the 12 animals on control diet were 4.33 + 0.18 gr compared to 3.56 + 0.26 for high dose (n=3) and 3.68 + 0.14 for low dose (n=8). The average renal cyst volume of the control diet animals was 0.53 + 0.06 ml compared to 0.27 + 0.05 for high dose and 0.33 + 0.09 for low dose. In the Wpk/Wpk animals, the kidney weights and renal cyst volumes of the animals on the high dose were not statistically different from the control diet animals while the animals fed the low dose were significantly different. Kidney weights of control versus low dose = 4.51 + 0.48 ml (n =11) versus 3.53 + 0.17 (n =10); renal cyst volume = 3.34 + 0.36 versus 2.57 + 0.14. Thus concentrations of PPARγ agonists that are below the doses used to treat diabetic patients are effective in slowing cyst growth in two models of PKD. At these low doses, the drugs are less likely to exert adverse side effects. We suggest that low dose PPARγ agonists may be effective life-long therapy for PKD patients.