The Role of Calcium and Cyclic AMP in PKD

ABSTRACT

Cyclic AMP (cAMP)-driven mechanisms are central to the pathogenesis of polycystic kidney disease (PKD). Cyclic AMP stimulates both fluid secretion and cell proliferation, making abnormal cAMP-regulated pathways key targets for PKD therapy. The success of vasopressin receptor blockade in lowering cAMP levels and ameliorating disease in murine models of PKD and in a recent clinical trial, argues that cAMP-regulated mechanisms are fundamental to cyst formation and disease progression. This chapter focuses on why cAMP is important to the disease process, and how the primary abnormality in PKD is the abnormal response of cells to cAMP rather than high levels of cAMP per se. This abnormal cAMP response is a consequence of the calcium environment being disrupted in PKD from loss of polycystin function. We have identified signaling mechanisms by which decreased intracellular calcium levels can transform normal cells into PKD-like cells. By treating normal renal epithelial cells with calcium channel blockers it has been possible to de-repress B-Raf, allowing its activation by cAMP and subsequent MEK/ERK activation to stimulate cell proliferation. Autosomal dominant PKD (ADPKD) cells can also be switched back to a normal phenotype by raising intracellular calcium. The abnormal response to cAMP is made worse by mechanisms that further raise intracellular cAMP, causing cAMP to stimulate cyst-filling fluid secretion in a cystic fibrosis transmembrane conductance regulator (CFTR)-dependent fashion. The abnormal PKD-like phenotype is likely a result of misregulated gene expression as well as disruption of a number of signaling pathways and altered cell cycle control, all resulting in a change in the phenotypic state. It is hypothesized that disruption of the calcium/calcineurin/nuclear factor of activated T-cells (NFAT) pathway would contribute to this phenotypic change by altering gene expression, and activating and upregulating CDK4 causing loss of cell cycle control, events that would cause cyst initiation, and that would promote cyst growth and enlargement.