Primary cilia of the kidney: from ciliopathy to urinary concentration
Article information
Most cells in the human body have either one or multiple cilia. The cilia are specialized microtubule-based projections from the cells’ apical surface, and they can be classified into motile and primary cilia. Motile cilia are typically distributed in the epithelial cells of the respiratory tract and reproductive system, and these cells have multiple cilia on their apical side [1]. In the kidney, the primary or non-motile cilium, a single or monocilium in one cell, is found on the parietal cells of the Bowman’s capsule and all tubular epithelial cells, with the exception of the intercalated cells in the collecting duct [2].
What roles do primary cilia play in the kidney? They detect chemical and mechanical cues and transduce extracellular information into downstream intracellular signaling mechanisms to maintain homeostasis, and the primary cilia are often referred to as cellular antennae [3]. It is unclear what the primary cilia specifically sense in the tubular lumen or urine flow. Instead, specific downstream signaling transduction pathways, including Hedgehog, Wnt, Notch, calcium, transforming growth factor-β, platelet-derived growth factor, G protein-coupled receptor, and mammalian target of rapamycin, were identified in the primary cilia [1, 4]. Moreover, dysfunction of the primary cilia, which contributes to the pathogenesis of a large spectrum of human genetic (e.g., polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome) and acquired (e.g., hypertension and diabetes mellitus) diseases are known as ciliopathies. Renal ciliopathies caused by mutations in cilia-associated proteins are characterized by the presence of kidney cysts that develop due to uncontrolled epithelial cell proliferation, growth, and polarity [3]. Table 1 summarizes the major renal ciliopathies that occur as a result of dysregulated primary cilium-dependent signaling.
Major renal ciliopathies
The structure of the primary cilium is based on an axoneme, which is encased within a membranous sheath that is continuous with the plasma membrane. The axoneme consists of nine bundles of microtubules anchored to the basal body [5]. The biogenesis of cilium can simply be explained by the process of axoneme elongation, and cilium length is modulated by both intrinsic and extrinsic factors. Intrinsic regulators of cilium length (e.g., Kif3a and Pitchfork) are initiated by structural and signaling molecules inside the cell. Extrinsic factors (e.g., fluid shear stress) originate from the extracellular environment, and they most likely regulate cilium length by affecting intracellular signaling [1].
In the current issue of Kidney Research and Clinical Practice, Kong et al. [6] reported an association between water balance and primary cilia length. As expected, they found that water deprivation enhanced urine concentration and upregulated aquaporin-2 (AQP2) in mice. In addition, the primary cilia length was shortened by water deprivation in association with deacetylation of α-tubulin and increased histone deacetylase 6 (HDAC6) activity. All these changes were blocked by tubastatin, a selective HDAC6 inhibitor.
For the stability and dynamics of primary cilia, axonemal microtubules, consisting of α- and β-tubulins, undergo a wide range of posttranslational modifications, including acetylation, glutamylation, glycosylation, ubiquitination, methylation, and phosphorylation. In particular, acetylation is a characteristic of α-tubulin in the cilia, but not in the cytoplasm [1]. Acetylated α-tubulin was also used in the current study [6] as the standard marker of cilia.
Regulators of cilium disassembly, such as the scaffolding protein HEF1, can activate Aurora A kinase, which in turn phosphorylates and stimulates HDAC6, thereby promoting the deacetylation of modified, stabilized tubulins within the axoneme [7]. According to Kong et al. [6], water deprivation acted as a regulator of cilium disassembly in mice. Arginine vasopressin might be a critical initiator of this process (Fig. 1). In polycystic kidney disease, the increased intracellular cyclic adenosine monophosphate (cAMP) level may lead to overexpression of HDAC6 [8]. Cilioplasmic and cytoplasmic cAMP levels may be affected by ciliary and intracellular signaling mechanisms, respectively [9].
A potential role of HDAC6 in urine concentration and primary cilia shortening.
Vasopressin signaling is activated by water deprivation via vasopressin receptor 2 and cAMP in the kidney. Intracellular cAMP level may be correlated with the HDAC6 activity [8]. HDAC6 induces both aquaporin-2 upregulation and primary cilium disassembly. The relationships between cilium assembly/disassembly and urine dilution/concentration remain to be clarified.
HDAC6, histone deacetylase 6; cAMP, cyclic adenosine monophosphate.
However, evidence is lacking to support the authors’ assumption that the shortening of cilia length is related to the antenna function of the primary cilia, sensing urine flow or osmolality. Regarding the AQP2 expression, the role of histone acetylation in AQP2 transcription might have been involved [10]. Consistent with the current study, vasopressin receptor 2 (V2R) was reported to be localized to the cilia in kidney epithelial cells, and the V2R antagonist tolvaptan increased the ciliary length in vitro [9]. Whether changes in primary cilium length occur in animals with water disturbance, including Brattleboro rats and V2R knockout mice, are needed to be investigated.
Notes
Conflicts of interest
The author has no conflicts of interest to declare.
Data sharing statement
The data presented in this study are available on request from the corresponding author.