scholarly journals Glis3 Is Associated with Primary Cilia and Wwtr1/TAZ and Implicated in Polycystic Kidney Disease

2009 ◽  
Vol 29 (10) ◽  
pp. 2556-2569 ◽  
Author(s):  
Hong Soon Kang ◽  
Ju Youn Beak ◽  
Yong-Sik Kim ◽  
Ronald Herbert ◽  
Anton M. Jetten
Keyword(s):  
Kidney Disease ◽  
Signaling Pathway ◽  
Polycystic Kidney Disease ◽  
Primary Cilium ◽  
Transcriptional Activation ◽  
Primary Cilia ◽  
Zinc Finger Protein ◽  
Critical Role ◽  
Renal Cysts ◽  
Polycystic Kidney

ABSTRACT In this study, we describe the generation and partial characterization of Krüppel-like zinc finger protein Glis3 mutant (Glis3zf/zf) mice. These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease. We demonstrate that Glis3 localizes to the primary cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway. Although Glis3zf/zf mice form normal primary cilia, renal cysts contain relatively fewer cells with a primary cilium. We further show that Glis3 interacts with the transcriptional modulator Wwtr1/TAZ, which itself has been implicated in glomerulocystic kidney disease. Wwtr1 recognizes a P/LPXY motif in the C terminus of Glis3 and enhances Glis3-mediated transcriptional activation, indicating that Wwtr1 functions as a coactivator of Glis3. Mutations in the P/LPXY motif abrogate the interaction with Wwtr1 and the transcriptional activity of Glis3, indicating that this motif is part of the transcription activation domain of Glis3. Our study demonstrates that dysfunction of Glis3 leads to the development of cystic renal disease, suggesting that Glis3 plays a critical role in maintaining normal renal functions. We propose that localization to the primary cilium and interaction with Wwtr1 are key elements of the Glis3 signaling pathway.

scholarly journals Exploring the Spectrum of Kidney Ciliopathies

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1099
Author(s):  
Matteo Santoni ◽  
Francesco Piva ◽  
Alessia Cimadamore ◽  
Matteo Giulietti ◽  
Nicola Battelli ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Signaling Pathways ◽  
Polycystic Kidney Disease ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Kidney Diseases ◽  
Ubiquitin Proteasome System ◽  
Polycystic Kidney ◽  
Ubiquitin Proteasome ◽  
Autosomal Dominant Polycystic Kidney

Ciliopathies are a group of multi-organ diseases caused by the disruption of the primary cilium. This event leads to a variety of kidney disorders, including nephronophthisis, renal cystic dysplasia, and renal cell carcinoma (RCC). Primary cilium contributes to the regulation of the cell cycle and protein homeostasis, that is, the balance between protein synthesis and degradation by acting on the ubiquitin-proteasome system, autophagy, and mTOR signaling. Many proteins are involved in renal ciliopathies. In particular, fibrocystin (PKHD1) is involved in autosomal recessive polycystic kidney disease (ARPKD), while polycystin-1 (PKD1) and polycystin-2 (PKD2) are implicated in autosomal dominant polycystic kidney disease (ADPKD). Moreover, primary cilia are associated with essential signaling pathways, such as Hedgehog, Wnt, and Platelet-Derived Growth Factor (PDGF). In this review, we focused on the ciliopathies associated with kidney diseases, exploring genes and signaling pathways associated with primary cilium and the potential role of cilia as therapeutic targets in renal disorders.

scholarly journals Modeling Neoplastic Growth in Renal Cell Carcinoma and Polycystic Kidney Disease

2021 ◽  
Vol 22 (8) ◽  
pp. 3918
Author(s):  
Cassandra Millet-Boureima ◽  
Stephanie He ◽  
Thi Bich Uyen Le ◽  
Chiara Gamberi
Keyword(s):  
Renal Cell Carcinoma ◽  
Kidney Disease ◽  
Cell Carcinoma ◽  
Polycystic Kidney Disease ◽  
Renal Cell ◽  
Primary Cilia ◽  
Genetic Model ◽  
Cell Metabolism ◽  
Neoplastic Cell ◽  
Polycystic Kidney

Renal cell carcinoma (RCC) and autosomal dominant polycystic kidney disease (ADPKD) share several characteristics, including neoplastic cell growth, kidney cysts, and limited therapeutics. As well, both exhibit impaired vasculature and compensatory VEGF activation of angiogenesis. The PI3K/AKT/mTOR and Ras/Raf/ERK pathways play important roles in regulating cystic and tumor cell proliferation and growth. Both RCC and ADPKD result in hypoxia, where HIF-α signaling is activated in response to oxygen deprivation. Primary cilia and altered cell metabolism may play a role in disease progression. Non-coding RNAs may regulate RCC carcinogenesis and ADPKD through their varied effects. Drosophila exhibits remarkable conservation of the pathways involved in RCC and ADPKD. Here, we review the progress towards understanding disease mechanisms, partially overlapping cellular and molecular dysfunctions in RCC and ADPKD and reflect on the potential for the agile Drosophila genetic model to accelerate discovery science, address unresolved mechanistic aspects of these diseases, and perform rapid pharmacological screens.

scholarly journals Molecular Pathways and Therapies in Autosomal-Dominant Polycystic Kidney Disease

Physiology ◽  
2015 ◽  
Vol 30 (3) ◽  
pp. 195-207 ◽  
Author(s):  
Takamitsu Saigusa ◽  
P. Darwin Bell
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Molecular Pathways ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Multiple Cysts ◽  
Review Current

Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can eventually lead to kidney failure. Studies investigating the role of primary cilia and polycystins have significantly advanced our understanding of the pathogenesis of PKD. This review will present clinical and basic aspects of ADPKD, review current concepts of PKD pathogenesis, evaluate potential therapeutic targets, and highlight challenges for future clinical studies.

Molecular genetics of renal ciliopathies

2021 ◽  
Author(s):  
Miguel Barroso-Gil ◽  
Eric Olinger ◽  
John A. Sayer
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Inherited Disorders ◽  
Disease Phenotypes ◽  
Renal Histology

Renal ciliopathies are a heterogenous group of inherited disorders leading to an array of phenotypes that include cystic kidney disease and renal interstitial fibrosis leading to progressive chronic kidney disease and end-stage kidney disease. The renal tubules are lined with epithelial cells that possess primary cilia that project into the lumen and act as sensory and signalling organelles. Mutations in genes encoding ciliary proteins involved in the structure and function of primary cilia cause ciliopathy syndromes and affect many organ systems including the kidney. Recognised disease phenotypes associated with primary ciliopathies that have a strong renal component include autosomal dominant and recessive polycystic kidney disease and their various mimics, including atypical polycystic kidney disease and nephronophthisis. The molecular investigation of inherited renal ciliopathies often allows a precise diagnosis to be reached where renal histology and other investigations have been unhelpful and can help in determining kidney prognosis. With increasing molecular insights, it is now apparent that renal ciliopathies form a continuum of clinical phenotypes with disease entities that have been classically described as dominant or recessive at both extremes of the spectrum. Gene-dosage effects, hypomorphic alleles, modifier genes and digenic inheritance further contribute to the genetic complexity of these disorders. This review will focus on recent molecular genetic advances in the renal ciliopathy field with a focus on cystic kidney disease phenotypes and the genotypes that lead to them. We discuss recent novel insights into underlying disease mechanisms of renal ciliopathies that might be amenable to therapeutic intervention.

The PI3K/Akt/mTOR pathway in polycystic kidney disease: A complex interaction with polycystins and primary cilium

2020 ◽  
Vol 66 ◽  
pp. 109468 ◽  
Author(s):  
Jean Piero Margaria ◽  
Carlo Cosimo Campa ◽  
Maria Chiara De Santis ◽  
Emilio Hirsch ◽  
Irene Franco
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilium ◽  
Complex Interaction ◽  
Mtor Pathway ◽  
Polycystic Kidney

Apoptosis in polycystic kidney disease: involvement of caspases

2000 ◽  
Vol 278 (3) ◽  
pp. R763-R769 ◽  
Author(s):  
Shujath M. Ali ◽  
Victoria Y. Wong ◽  
Kristine Kikly ◽  
Todd A. Fredrickson ◽  
Paul M. Keller ◽  
...  
Keyword(s):  
Cell Death ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Apoptotic Cell ◽  
Renal Cysts ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Homozygous Mutation ◽  
Polycystic Kidney ◽  
Apoptosis Pathway ◽  
Cystic Kidneys

Polycystic kidney disease (PKD) is characterized by the development of large renal cysts and progressive loss of renal function. Although the cause of the development of renal cysts is unknown, recent evidence suggests that excessive apoptosis occurs in PKD. With the use of terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, we have confirmed the presence of apoptotic bodies in cystic kidneys of congenital polycystic kidney (cpk) disease mice carrying a homozygous mutation at 3 wk of age. Apoptosis was localized primarily to the interstitium with little evidence of cell death in cyst epithelium or noncystic tubules. In addition, we observed that the expression of various caspases, bax and bcl-2, was upregulated in cystic kidneys. With the use of various substrates in enzyme activity assays, we have demonstrated a greater than sevenfold increase in caspase 4 activity and a sixfold increase in caspase 3 activity. These data suggest that there is a caspase-dependent apoptosis pathway associated with PKD and support the hypothesis that apoptotic cell death contributes to cyst formation in PKD.

Sign in / Sign up

Export Citation Format

Share Document