Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1

Abstract

The root cause for most cases of autosomal-dominant polycystic kidney disease (ADPKD) is mutations in the polycystin-1 (PC1) gene. While PC1 has been implicated in a perplexing variety of protein interactions and signaling pathways, what its normal function is and why its disruption leads to the proliferation of renal epithelial cells are unknown. Recent results suggest that PC1 is involved in mechanotransduction by primary cilia measuring the degree of luminal fluid flow. PC1 has also recently been shown to regulate the mTOR and signal transducers and activators of transcription (STAT) 6 pathways. These two pathways are normally dormant in the healthy kidney but are activated in response to injury and appear to drive a proliferative repair response. This review develops the idea that a critical function of PC1 and primary cilia in the adult kidney may be to sense renal injury by detecting changes in luminal fluid flow and to trigger proliferation. Constitutive activation of these pathways in ADPKD would lead to the futile attempt to repair a nonexisting injury, resulting in cyst growth. The existence of many known cellular and molecular similarities between renal repair and ADPKD supports this model.