Cilia in cystic kidney and other diseases

Abstract

Epithelial cells lining the ducts and tubules of the kidney nephron and collecting duct have a single non-motile cilium projecting from their surface into the lumen of the tubule. These organelles were long considered vestigial remnants left as a result of evolution from a ciliated ancestor, but we now recognize them as critical sensory antennae. In the kidney, the polycystins and fibrocystin, products of the major human polycystic kidney disease genes, localize to this organelle. The polycystins and fibrocystin, through an unknown mechanism, monitor the diameter of the kidney tubules and regulate the proliferation and differentiation of the cells lining the tubule. When the polycystins, fibrocystin or cilia themselves are defective, the cell perceives this as a pro-proliferative signal, which leads to tubule dilation and cystic disease. In addition to critical roles in preventing cyst formation in the kidney, cilia are also important in cystic and fibrotic diseases of the liver and pancreas, and ciliary defects lead to a variety of developmental abnormalities that cause structural birth defects in most organs.

Keywords: Cilia; Intraflagellar transport; Kidney; Polycystic kidney disease.

Figure 1.. Cystic Disease Caused by Loss of Polycystin-2 or Ift20.

During the development of cystic kidney disease, the normal tubular architecture seen in control animals is lost and large fluid filled cysts (C) form. The loss of polycystin-2 does not affect cilia formation (acetylated alpha tubulin, red; gamma tubulin, white) and the cilia remain in the cysts whereas the loss of Ift20 prevents cilia formation. Green (Dolichos Biflorus Agglutinin) marks collecting ducts. Scale bar is 20 microns.

Figure 2.. Structure of the cilium, centriole and centrosome.

The cilium is composed of 1000 or more proteins organized around a microtubule-based cytoskeleton called the axoneme and in the ciliary membrane, an extension of the plasma membrane that surrounds the axoneme. The microtubules are templated from the mother centriole or basal body, which is embedded within the centrosome. In addition to the centrioles, the centrosome also contains microtubule binding and nucleating proteins and a variety of signal transduction components. The human axoneme has a stereotypical arrangement of microtubules. These are referred to as 9+2 or 9+0 depending on whether the central pair is present or not. The central pair is critical for generating complex waveforms and is present in most motile cilia but is absent in non-motile cilia. This structure is either missing or significantly underdeveloped in the motile cilia of the embryonic node, which have a relatively simple waveform. Force generation is provided by the inner and outer dynein arms in response to signals generated by the central pair and transmitted through the radial spokes. These structures are missing from non-motile cilia but outer dynein arms are found in nodal cilia. The cilium is anchored to the plasma membrane through appendages from the centriole called the transition fibers and through an extensive network of cytoskeletal to membrane linking proteins at the base of the cilium. The latter structure is called the transition zone and appears to be an important part of the diffusional barrier that separates the ciliary membrane compartment from the bulk plasma membrane. Ciliary assembly is driven by the intraflagellar transport (IFT) system that involves the movement of large protein complexes along the ciliary axoneme. The large protein complexes or IFT particles, are built from the IFA-A. IFT-B, and BBSome subcomplexes. The outward movement (anterograde direction) is powered by kinesin-2 while the inward movement (retrograde direction) is powered by cytoplasmic dynein 2. The IFT particles are motor adaptors that are needed to couple the molecular motors to cargos made in the cell body and transported into the cilium. Figure prepared with Biorender.

Figure 3.. Clinical features of human ciliopathy syndromes with renal involvement.

(A) MRI image of enlarged polycystic kidneys in autosomal dominant polycystic kidney disease. (B) Ultrasound image showing a “salt and pepper” pattern and cysts in an enlarged autosomal recessive polycystic kidney disease kidney. (C) Small hyperechogenic kidney in nephronophthisis with a single cysts (arrow) visualized by ultrasound. (D) Substantially narrowed thorax in an infant with Jeune asphyxiating thoracic dystrophy. (E) Polydactyly of the feet observed in Jeune asphyxiating thoracic dystrophy. (F) Mildly narrowed thorax in a boy with Jeune asphyxiating thoracic dystrophy / Mainzer-Saldino Syndrome resulting from biallelic IFT140 dysfunction. (G) Mildly narrowed thorax, facial dysmorphism with low set ears, small mouth, downwards slanting palpebral fissures, sparse hair, dolichocephalous due to craniosynostosis and (H) teeth abnormalities in Sensenbrenner syndrome or Cranioectodermal dysplasia. (I) Facial features and obesity in Bardet-Biedl-Syndrome. (J) Retinal degeneration occurs in Jeune asphyxiating thoracic dystrophy / Mainzer-Saldino Syndrome, Cranioectodermal dysplasia and Bardet-Biedl-Syndrome. (K) Histological pattern of a renal biopsy in Jeune asphyxiating thoracic dystrophy with renal disease / Mainzer-Saldino Syndrome due to biallelic IFT172 dysfunction (hematoxylin and eosin staining) showing ectatic tubules but no larger cysts. Image A was a courtesy of Dr. Gerd Walz, University Hospital Freiburg. Image B was a courtesy of Dr. Martin Pohl, University Hospital Freiburg Images C-K have been reprinted with permission [171], [78], [100], [171], [95], [172], [173], [78] respectively.