ABSTRACT
The development and progression of renal cysts appears to be driven by reduced cellular calcium and increased cyclic adenosine monophosphate (cAMP) from G-protein-coupled receptors. To test whether treatment with a calcimimetic that stimulates the G-protein-coupled calcium-sensing receptor might normalize cystic epithelial cell intracellular calcium and cAMP, thereby inhibiting cyst progression, we used pcy mice. These animals develop cysts principally in the collecting duct, as do humans with nephronophthisis (NPHP). We administered the calcimimetic R-568 mixed in their food at early or late stages in the pathogenesis of cyst formation. The treatment reduced cyst enlargement, and the early treatment inhibited development of renal fibrosis. Although the effect of later treatment was more modest, both stages of the disease responded positively to treatment. Additionally, R-568 decreased total kidney cAMP in the pcy mice and, in vitro, decreased cAMP levels and cell proliferation, while increasing intracellular calcium in immortalized human autosomal recessive polycystic kidney disease renal epithelial cells. The latter two effects were unique to R-568 and not replicated by raising extracellular calcium. Thus, treating pcy mice with R-568 was effective in reducing cyst progression in this rodent model of NPHP. Direct studies will be needed to determine whether these results can be applied to the human disease.
Subject(s)
Aniline Compounds/pharmacology , Calcimimetic Agents/pharmacology , Kidney Diseases, Cystic/pathology , Kidney Diseases, Cystic/prevention & control , Animals , Cell Line , Cell Proliferation/drug effects , Cyclic AMP/metabolism , Disease Models, Animal , Female , Humans , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/metabolism , Kinesins/genetics , Male , Mice , Mice, Mutant Strains , Mutation, Missense , Phenethylamines , Polycystic Kidney, Autosomal Recessive/drug therapy , Polycystic Kidney, Autosomal Recessive/metabolism , Polycystic Kidney, Autosomal Recessive/pathology , Propylamines , Receptors, Calcium-Sensing/agonistsABSTRACT
Polycystic kidney disease (PKD) is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney tubules and liver bile ducts. Currently, the clinical management of PKD is limited to cyst aspiration, surgical resection or organ transplantation. Based on an observation that PPARγ agonists such as pioglitazone and rosiglitazone decrease mRNA levels of a Cl(-) transport protein, CFTR (cystic fibrosis transmembrane conductance regulator), and the Cl(-) secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7- or 14-week pioglitazone feeding regimen inhibits renal and hepatic bile duct cyst growth in the PCK rat, a rodent model orthologous to human PKD. These studies provide proof of concept for the mechanism of action of the PPARγ agonists and suggest that this class of drugs may be effective in controlling both renal and hepatic cyst growth and fibrosis in PKD.
ABSTRACT
The rat Pck gene is orthologous to the human PKHD1 gene responsible for autosomal recessive polycystic kidney disease (ARPKD). Both renal and hepatic fibrocystic pathology occur in ARPKD. Affected humans have a variable rate of progression, from morbidly affected infants to those surviving into adulthood. This study evaluated the PCK rat, a model of slowly progressive ARPKD. This model originated in Japan and was rederived to be offered commercially by Charles River Laboratories (Wilmington, MA). Previous studies have described the basic aspects of PCK pathology from privately held colonies. This study provides a comprehensive characterization of rats from those commercially available. Rats were bred, maintained on a 12:12 hr light/dark cycle, fed (7002 Teklad), and water provided ad libitum. Male and female rats were evaluated from 4 through 35 weeks of age with histology and serum chemistry. As the hepatorenal fibrocystic disease progressed beyond 18 weeks, the renal pathology (kidney weight, total cyst volume) and renal dysfunction (BUN and serum creatinine) tended to be more severe in males, whereas liver pathology (liver weight as % of body weight and hepatic fibrocystic volume) tended to be more severe in females. Hyperlipidemia was evident in both genders after 18 weeks. Bile secretion was increased in PCK rats compared with age-matched Sprague Dawley rats. The PCK is an increasingly used orthologous rodent model of human ARPKD. This characterization study of hepatorenal fibrocystic pathology in PCK rats should help researchers select stages of pathology to study and/or monitor disease progression during their longitudinal studies.
