Pathophysiology of PKD
Recent evidence suggests that the primary abnormality leading to cyst formation in both the autosomal dominant and recessive forms of PKD is related to defects in cilia-mediated signaling activity.Specifically, PKD is thought to result from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body.In the kidney, primary cilia have been found to be present on most cells of the nephron, projecting from the apical surface of the renal epithelium into the tubule lumen.In response to fluid flow over the renal epithelium, the primary cilium is bent, resulting in a flow-induced increase in intracellular calcium.
In a 2009 review of the pathogenesis of PKD, Patel et al discuss the accumulating evidence supporting the role of the primary cilium in PKD. They note the identification of polycystin-1, polycystin-2, and fibrocystin, the proteins associated with ADPKD and ARPKD, within the primary cilia and basal body of renal tubular epithelia, suggesting that defects in these proteins and subsequent cilia formation may lead to PKD. The same has been found to be true for other cyst-producing conditions, including nephronophthisis and Bardet–Biedl syndrome, where causative proteins have also been localized to the primary cilia and basal body. Additional evidence for the role of the primary cilium in PKD comes from the finding that transgenic mice with kidney-specific knockouts of Kif3a, a motor protein subunit required for cilia formation, produce renal cysts in mice similar to those seen in human PKD. While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Hedgehog, Wnt/β-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP).
PCP refers to the coordinated orientation of cells making up most of the organs of the body in a plane vertical to the apical/basal axis of the cell sheet. PCP is thought to play an essential role in the organogenesis of numerous organ systems through direction of cell migration, polarized cell division, and cellular differentiation, with disruption of this organization thought to play an important role in the etiology of PKD. The role of PCP in the etiology of PKD was originally demonstrated by Fischer et al who found that PCK rats (carrying mutations in PKHD1), had randomized patterns of cell division, contributing to tubular dilation and cyst formation. This was in comparison to wild-type renal tubules, which were found to divide along an axis roughly parallel to the longitudinal axis of the tubule. This polarity is thought to be regulated by the primary cilium, as mice with the inactivated Kif3a gene have also been found to display disorganized cell division, suggesting disrupted PCP. Similar findings have been found with inactivation of other genes required for ciliogenesis, strengthening the role of the primary cilium in the regulation of PCP. Recent evidence suggests that disrupted PCP may play a role solely in the pathogenesis of ARPKD, as mouse models of PKD1 and PKD2 mutations have been found to lose cell-oriented division only after cyst formation has begun, unlike models of PKHD1.
Accordingly, with mutations in PKD1, PKD2, or PKHD1, function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades that produce dedifferentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity. These signaling pathways have been found to include cAMP-activated, Wnt signaling, and mammalian target of rapamycin (mTOR) pathways, the discoveries of which have greatly expanded the number of potential therapeutic targets for the disease. Ultimately, cyst growth and expansion compresses renal vessels and leads to intrarenal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS), in turn producing progressive cyst expansion, increased systemic vascular resistance, sodium retention, and renal fibrosis.
Vascular manifestations of ADPKD are thought to also be related to abnormal functioning of polycystin-1 and polycystin-2, which additionally have been found to be expressed in vascular smooth muscle and endothelium. Polycystin-1 and polycystin-2 associate with one another and form a ‘receptor-ion channel complex’ on the membrane of primary cilia of renal epithelial cells as well as endothelial cells. Here, luminal sheer stress is thought to be sensed by polycystin-1, opening the calcium-permeable channel polycystin-2 which leads to a series of calcium-dependent signaling cascades. When this mechanosensory function is lost in ADPKD, calcium signaling is disrupted, contributing to cyst formation and numerous vascular alterations. More recently, studies have suggested a role for polycystins in pressure-sensing within arterial myocytes, showing that the ratio of polycystin-1 to polycystin-2 regulates the opening of stretch-activated cation channels, modulating the arterial response to changes in intraluminal pressure. Additional work has revealed that a reduced dose of PKD1 in mouse models is associated with vascular dysfunction, resulting in age-dependent increases in vascular reactivity. This reactivity is thought to be the result of altered intracellular calcium homeostasis and compensatory changes in transport proteins involved in calcium signaling, producing alteration of endothelium-dependent relaxation and increased systolic blood pressures. Accordingly, PKD1 haploinsufficiency, and dosages of polycystin-1 and -2, are thought to play an important role in vascular smooth muscle intracellular calcium homeostasis, and thus in the pathogenesis of vascular changes seen in ADPKD.