The role of cilia in the pathogenesis of cystic kidney disease

Abstract

Purpose of review Primary (immotile) cilia are specialized organelles present on most cell types. Almost all of proteins associated with a broad spectrum of human cystic kidney diseases have been localized to the region in or around the cilia. Abnormal cilia structure and/or function have been reported in animal models and human cystic kidneys. The goal of this review is to discuss current understanding of the mechanisms by which abnormal genes/proteins and cilia interact to potentially influence renal cystogenesis. Recent findings Novel direct recording of cilia calcium levels/channel activity suggest that cilia form a calcium-mediated signaling microenvironment separate from the cytoplasm, which could provide a mechanism for cilia-specific downstream signaling. Genetic-based studies confirm that cilia are not required for cystogenesis but modulate cystic kidney disease severity through a novel, undefined mechanism. Mechanisms by which both cilia-associated and non-cilia associated proteins can alter cilia structure/function have also been identified. Summary Considerable progress has been made in defining the mechanisms by which abnormal genes and proteins affect cilia structure and function. However, the exact mechanisms by which these interactions cause renal cyst formation and progression of cystic kidney disease are still unknown.

Primary Cilia and Calcium Signaling Interactions

“…Research on abnormal cilia mechano-function in the kidneys has centered around flow-induced changes in intracellular Ca 2+ ; when either PC-1 or PC-2 is altered, the expected elevation in intracellular Ca 2+ is abolished, thereby altering downstream signaling cascades and activating pro-cystogenic pathways. Interestingly, this has been observed in a cilia-less mutant renal cell line, orpk, suggesting that a loss of protein function or a loss of the cilia structure dysregulates Ca 2+ entry into the cell and promotes aberrant tissue maintenance [ 38 ]. Similarly, cilia on vascular endothelial cells are also responsible for detecting fluid shear stress in order to maintain blood pressure.…”

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

“…In autosomal dominant PKD, the most common form of PKD, mutations are commonly found in two genes: polycystin 1, a large transmembrane protein associated with primary cilia; and polycystin 2, a TRP-family channel. The orthodoxy is thus that defects in the primary cilium of renal cells confers problems with apicobasal polarity (Yoder 2007;Dell 2015), although the subtlety and complexity of the connection between cilia and PKD is only now becoming clear (Dell 2015). Unfortunately, while Drosophila has a gene similar to Pkd2, it lacks primary cilia in most cells, so a direct renal model is not available.…”

The Role of Wnt Signalling in Chronic Kidney Disease (CKD)

“…Both JS and MGS are inherited in an autosomal recessive pattern and have been categorised alongside ADPKD, ARPKD and NPHP as 'ciliopathies', a term which denotes defects in primary cilia [20,21]. Primary cilia have been implicated in kidney development and disease and are linked to proteins that are associated with cystic renal diseases, including the diseases mentioned above [22]. Signalling via the primary cilium is also thought to be a crucial process and evidence has found that defects in cilia can impact cilia-associated signalling pathways, including Wnt signalling [23].…”