Autosomal Dominant Polycystic Kidney - Pathophysiology

Pathophysiology

Recent studies in fundamental cell biology of cilia and flagella using experimental model organisms such as the round worm Caenorhabditis elegans and the mouse Mus musculus have shed light on how PKD develops in human patients.

All cilia and flagella are constructed and maintained, by the process of intraflagellar transport, a cellular function that is also essential for the insertion of proteins at specific sites along cilia and flagella membranes. These inserted membrane proteins can initiate environmental sensing and intracellular signaling pathways. They play a special role in the cilia of renal epithelial cells, and are thought to be critical for normal renal cell development and function and are sorted out and localized to the cilia of renal epithelial cells by the aforementioned intraflagellar transport mechanism. Ciliated epithelial cells line the lumen of the urinary collecting ducts and sense the flow of urine. Failure in flow-sensing signaling results in programmed cell death (apoptosis) of these renal epithelial cells, producing the characteristic multiple cysts of PKD. PKD may result from mutations of signaling and environmental sensing proteins, or failure in intraflagellar transport.

Two PKD genes, PKD1 and PKD2, encode membrane proteins that localize to a non-motile cilium on the renal tube cell. Polycystin-2 encoded by PKD2 gene is a calcium channel that allows extracellular calcium ions to enter the cell. Polycystin-1, encoded by PKD1 gene, is thought to be associated with polycystin-2 protein and regulates polycystin-2's channel activity. The calcium ions are important cellular messengers, which trigger complicated biochemical pathways that lead to quiescence and differentiation. Malfunctions of polycystin-1 or polycystin-2 proteins, defects in the assembly of the cilium on the renal tube cell, failures in targeting these two proteins to the cilium, and deregulations of calcium signaling all likely cause the occurrence of PKD.