Apoptosis in Polycystic Kidney Disease: From Pathogenesis to Treatment

ABSTRACT

Apoptosis plays an important role in many developmental processes and contributes to cell and tissue homeostasis. Induction of apoptosis can involve the "intrinsic pathway", which is activated by diverse stress signals, and the "extrinsic pathway", which is activated by proapoptotic receptor signals at the cell surface. Excessive or aberrant apoptosis is a crucial factor in many human disorders, including polycystic kidney disease (PKD). Renal cyst formation is caused by dysregulation of cell proliferation, involving diverse and poorly understood molecular mechanisms. Elevated apoptosis of tubular epithelial cells has been described in autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD), as well as in animal models of PKD. It has been suggested that the dysregulation of apoptosis contributes to cystogenesis of PKD and is associated with the progressive loss of normal nephrons. Inhibition of apoptosis has been shown to delay renal cyst growth in some animal models of PKD. However, increased apoptosis is not a feature in cystic kidneys from Pkd1 mutant mice and inducing apoptosis of the cystic epithelial cells by activation of intrinsic or extrinsic signaling pathways has been shown to slow disease progression with or without inhibition of proliferation. In this chapter, we discuss the positive and negative roles of apoptosis in PKD and the associated molecular mechanisms in regulating cystic renal epithelial cell apoptosis during cyst development.