9. Ciliopathies: an insight into some clinical consequences of impaired ciliary function

#### 9.1. Polycystic kidney disease

As indicated above, the relevance of the primary cilium function has been well established in the kidney, as evidenced in polycystic kidney disease [37, 77, 78]. Also, previous reports suggest that the outcome of I/R in kidneys is associated with the change of primary cilia length [17]. Physiologically, urinary flow through the nephron is a highly variable process. In the short term, flow changes can be caused by variations in glomerular filtration rate [79], tubuloglomerular feedback [80] and fluid absorption along the nephron [79]. In the long term, urinary flow fluctuations can be caused by a high salt [81] or high protein diet [82], as well as due to hypertension [83] or early stages of diabetes [84]. Variations in luminal urinary flow alter the mechanical forces (shear stress, stretch and pressure) that affect epithelial cells in the nephron.

Polycystic kidney disease is a genetic disease characterized by bilateral enlarged cystic kidneys. It is caused by mutations of genes encoding for PKD1 and PKD2 linked to polycystic kidney disease type 1 (pkd1) and polycystic kidney disease type 2, respectively [37, 77, 78]. The frequencies of cardiovascular complications are very high in polycystic kidney disease patients. Hypertension occurs in 50–70% of patients even before any substantial kidney disorder [85]. Polycystic kidney disease has been associated with abnormalities in FSS sensing due to primary cilia dysfunction [36]. Mechanistically, polycystic kidney disease patients exhibit impairment of endotheliumdependent relaxation and a decrease of eNOS activity, impaired release of NO and, therefore, endothelial dysfunction [86]. Furthermore, polycystic kidney disease has been associated to the inability of renal epithelia [87] or vascular endothelia [9] to induce Ca2+ influx in response to FSS. Endothelial cells isolated from mice and humans with polycystic kidney disease lack PKD1 and/ or PKD2 in the primary cilium and fail to produce NO in response to FSS [2, 9, 29].

Abnormal PKD2 function or expression has been associated with hypertension [88]. Mutations of pkd2 gene abolish Ca2+ and NO increases in endothelial cells showing that PKD2 mediates FSS sensing in endothelial cells [29]. In addition, PKD2 sensory function as a Ca2+ channel depends on its localization at the primary cilium and on PKD1. Thus, impaired function and expression of PKD2 are associated with endothelial dysfunction. Interestingly, prolonged exposure of endothelial cells to high FSS induces the disassembly of cilia [28] and inactivation of PKD1 by proteolytic cleavage [9], reducing the ability of endothelial cells to properly sense alterations in blood pressure.
