Banga A, Flaig S, Lewis S, Winfree S, Blazer-Yost BL. Epinephrine stimulation of anion secretion in the Calu-3 serous cell model.

Background and Objectives:The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD). Materials and Methods: The PCK rat is a slowly progressing cystic model while the Wpk -/-rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4-28). Wpk -/-rats were fed with pharmacological (2.0 mg/kg BW) and sub-pharmacologic (0.2 mg/kg BW) doses of pioglitazone from day 5 to 18. At termination, kidney weights of treated versus untreated cystic animals were used to determine efficacy. The current studies were also compared with previous studies containing higher doses of PPARγ agonists. The concentrations used in the animals were calculated with reference to equivalent human doses for both drugs. Results:The current studies demonstrate: 1) that low, pharmacologically relevant, doses of the PPARγ agonists effectively inhibit cyst growth; 2) there is a class action of the drugs with both commercially available PPARγ agonists, rosiglitazone, and pioglitazone, inhibiting cyst growth; 3) the drugs showed efficacy in two different preclinical cystic models. In the PCK rat, animals fed with a sub-pharmacological dose of rosiglitazone for 24 weeks had significantly lower kidney weights than untreated animals (3.68 ± 0.13 g vs. 4.17 ± 0. 11 g, respectively, P < 0.01) while treatment with a pharmacologic dose had no significant effect on kidney weight. The rapidly progressing Wpk -/-rats were fed with pharmacological and sub-pharmacologic doses of pioglitazone from day 5 to 18 and the kidneys were compared with non-treated, cystic animals. Kidney weights on the pharmacologic dose were not statistically lower than the untreated animals while rats fed a sub-pharmacologic dose showed a significant decrease compared with untreated animals (3.35 ± 0.15 g vs. 4.55 ± 0.46 g, respectively, P = 0.045). Conclusion: Concentrations of PPARγ agonists below the human equivalent diabetic doses are effective in slowing cyst growth in two rodent models of PKD.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the slow growth of multiple fluid-filled cysts predominately in the kidney tubules and liver bile ducts. Elucidation of mechanisms that control cyst growth will provide the basis for rational therapeutic intervention. We used electrophysiological methods to identify lysophosphatidic acid (LPA) as a component of cyst fluid and serum that stimulates secretory Cl- transport in the epithelial cell type that lines renal cysts. LPA effects are manifested through receptors located on the basolateral membrane of the epithelial cells resulting in stimulation of channel activity in the apical membrane. Concentrations of LPA measured in human ADPKD cyst fluid and in normal serum are sufficient to maximally stimulate ion transport. Thus, cyst fluid seepage and/or leakage of vascular LPA into the interstitial space are capable of stimulating epithelial cell secretion resulting in cyst enlargement. These observations are particularly relevant to the rapid decline in renal function in late-stage disease and to the “third hit” hypothesis that renal injury exacerbates cyst growth.

Polycystic kidney diseases (PKD) are genetic disorders characterized by fluid‐filled cysts in kidney tubules and liver bile ducts. Cyst enlargement is due, at least in part, to Cl− secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel. Previous studies demonstrated that PPARγ agonists, pioglitazone and rosiglitazone, insulin sensitizing drugs used to treat diabetes, inhibit Cl− secretion in collecting duct cells via decreased CFTR synthesis. Our preclinical studies showed that pioglitazone and low (0.04 mg/kg BW) dose rosiglitazone inhibited cyst growth in the PCK rat model of PKD. The current study was designed to study the effect of the agonists in an alternative PDK model and to determine if CT scans could be used to track the progress of disease and drug therapy. W‐WPK rats, a rapidly progressing model, were fed a diet containing pioglitazone (20 and 2 mg/kg BW) from day 5 to 18. In agreement with previous studies, the lower dose was the most effective in reducing cyst growth. The CT scans proved to be effective in determining the progress of the disease and yielded results that correlated well with post‐sacrifice analyses. Funding: CTSI grant ‐ IUSM