Primary Cilia in Cystic Kidney Disease

Abstract

Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined. Autosomal Dominant Polycystic Kidney Disease is the most common renal cystic disease, caused by disruption of polycystin-1 and polycystin-2 transmembrane proteins, which evidence suggests must localize to primary cilia for proper function. To understand how the absence of these proteins in primary cilia may be remediated, we review intracellular trafficking of polycystins to the primary cilium. We also examine the controversial mechanisms by which primary cilia transduce flow-mediated mechanical stress into intracellular calcium. Further, to better understand ciliary function in the kidney, we highlight the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease.

Ciliary Genes in Renal Cystic Diseases

“…All the above mentioned studies support the unifying theory of renal cystogenesis, coined more than 15 years ago, and further developed in later studies [17,136,137] According to this concept, mutations in genes expressed in primary cilia, basal bodies and centrosomes lead to dysfunction of cilia, thereby contributing to cell differentiation, stimulated proliferation and fluid secretion, as well as increased apoptosis of tubular cells, ultimately leading the development of cystic disease [17,136,137]. Further studies suggested that human ciliopathies could be caused by sorting defects at the transition zone and the ciliary gate [56].…”

“…Further studies suggested that human ciliopathies could be caused by sorting defects at the transition zone and the ciliary gate [56]. It was initially proposed that the key molecular events contributing to cystogenesis are increased intracellular cAMP [17], or activation of MAPK/ERK and mTOR pathways [138][139][140]. However, studies in murine ADPKD models excluded the causative role of these signaling cascades and demonstrated that formation of cysts is rather triggered by other cilia-dependent pathways [138].…”

“…The daughter centriole results from duplication of mother centriole during S phase[4]). The arrows indicate the key structural cilium elements (the axoneme, transition zone and basal body) as well as proteins involved in kidney ciliopathies and renal cell carcinoma (RCC)[4,5,17,18].…”

Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney

“…Two such spatially confined subcellular compartments are lipid rafts and cilia. In particular, the latter has been implicated in PKD (Avasthi et al, 2017;Ma et al, 2017;Pala et al, 2017). Both GPCRs and polycystin 1 are present in cilia (Yoder et al, 2002;Schou et al, 2015;Hilgendorf et al, 2016).…”

Prothymosin α promotes STAT3 acetylation to induce cystogenesis in Pkd1‐deficient mice

“…Abnormality of the polycystic kidney disease (Pkd) 1 or Pkd2 genes, which encode polycystin-1 and polycystin-2, respectively, causes ADPKD; both polycystin-1 and polycystin-2 are transmembrane proteins and function in cell-cell/matrix interactions, tissue development, mechanical sensors, and calcium signaling (2). Cystic epithelial cells exhibit various physiologic aberrations, such as abnormal proliferation of renal epithelial cells (1), dysfunction of primary cilia (3)(4)(5), and dysregulation of extracellular matrix remodeling (6). In the molecular pathologic mechanism of cystic epithelia, several signal transduction pathways are known to be abnormal in cyst progression, including epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), TGF-b/Smad, and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (7), and several molecules targeting these signaling pathways have been developed to decrease cyst expansion in mice PKD models.…”