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. 2013 Mar;28(3):518-26.
doi: 10.1093/ndt/gfs524. Epub 2013 Jan 12.

The Ciliary Flow Sensor and Polycystic Kidney Disease

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Free PMC article

The Ciliary Flow Sensor and Polycystic Kidney Disease

Fruzsina Kotsis et al. Nephrol Dial Transplant. .
Free PMC article

Abstract

Since the discovery that proteins mutated in different forms of polycystic kidney disease (PKD) are tightly associated with primary cilia, strong efforts have been made to define the role of this organelle in the pathogenesis of cyst formation. Cilia are filiform microtubular structures, anchored in the basal body and extending from the apical membrane into the tubular lumen. Early work established that cilia act as flow sensors, eliciting calcium transients in response to bending, which involve the two proteins mutated in autosomal dominant PKD (ADPKD), polycystin-1 and -2. Loss of cilia alone is insufficient to cause cyst formation. Nevertheless, a large body of evidence links flow sensing by cilia to aspects relevant for cyst formation such as cell polarity, Stat6- and mammalian target of rapamycin signalling. This review summarizes the current literature on cilia and flow sensing with respect to PKD and discusses how these findings intercalate with different aspects of cyst formation.

Figures

FIGURE 1:
FIGURE 1:
Flow transmits polarized information to the centriolar apparatus. (a) In the epidermis of Xenopus embryos, motile 9+2 cilia generate unidirectional flow (pink arrow) which is necessary for the polarization of the basal bodies (mother centriole—blue) from which the cilia originate [69]. Polarization is visualized by asymmetric localization of the basal foot, a basal body appendage (purple triangle). (b) In renal epithelial cells, passive bending of monocilia through flow (pink arrow) results in calcium transients and preferential centriole movements along the flow axis [33]. (c) In the absence of flow, or in cells expressing a polycystin-2 mutant preventing flow-induced calcium increases, no orientation bias of centriole movements is observed.
FIGURE 2:
FIGURE 2:
Lkb1 localizes to cilia. Bending of the cilium by flow causes increased phosphorylation of the Lkb1 target AMPK at the basal body [30]. Activated AMPK inhibits mTORC1 and decreases the cell size. In addition, mTORC1 activity regulates the cilia length [92].
FIGURE 3:
FIGURE 3:
Model of a feedback loop to maintain shear stress sensing through flow-induced mTORC1 regulation. (a) During high flow, mTORC1 activity is decreased resulting in short cilia. (b) During low flow, activation of mTORC1 would result in longer cilia, which increases the amplification of the flow signal.
FIGURE 4:
FIGURE 4:
Hypothetical model showing how the cell size may affect shear stress and tubular diameter. Increased mTORC1 activity leads to bigger cell size. In the case of a fixed tubular basement membrane diameter, luminal shear stress will increase. Maintaining a normal level of shear stress requires an increase of tubular basement membrane diameter. Since the deficient ciliary flow sensor is responsible for increased mTORC1 activity and cell size dysregulation, this model requires an alternate mode of shear stress sensing.

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