scholarly journals Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella

2000 ◽  
Vol 151 (3) ◽  
pp. 709-718 ◽  
Author(s):  
Gregory J. Pazour ◽  
Bethany L. Dickert ◽  
Yvonne Vucica ◽  
E. Scott Seeley ◽  
Joel L. Rosenbaum ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Disease Gene ◽  
Intraflagellar Transport ◽  
Polycystic Kidney ◽  
Subunit Protein ◽  
Human Genes ◽  
Protein Particles ◽  
Cilia And Flagella

Intraflagellar transport (IFT) is a rapid movement of multi-subunit protein particles along flagellar microtubules and is required for assembly and maintenance of eukaryotic flagella. We cloned and sequenced a Chlamydomonas cDNA encoding the IFT88 subunit of the IFT particle and identified a Chlamydomonas insertional mutant that is missing this gene. The phenotype of this mutant is normal except for the complete absence of flagella. IFT88 is homologous to mouse and human genes called Tg737. Mice with defects in Tg737 die shortly after birth from polycystic kidney disease. We show that the primary cilia in the kidney of Tg737 mutant mice are shorter than normal. This indicates that IFT is important for primary cilia assembly in mammals. It is likely that primary cilia have an important function in the kidney and that defects in their assembly can lead to polycystic kidney disease.

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.

Autosomal recessive polycystic kidney disease

2015 ◽  
Author(s):  
Carsten Bergmann ◽  
Klaus Zerres
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Primary Cilia ◽  
Transmembrane Protein ◽  
Phenotypic Variability ◽  
Amino Acid Type ◽  
Polycystic Kidney ◽  
Exact Function ◽  
The Individual

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality with variable disease expression. Many patients manifest peri- or neonatally with a mortality rate of 30–50%, whereas others survive to adulthood with only minor clinical features. ARPKD is typically caused by mutations in the PKHD1 gene that encodes a 4074-amino acid type 1 single-pass transmembrane protein called fibrocystin or polyductin. Fibrocystin/polyductin is among other cystoproteins expressed in primary cilia, basal bodies, and centrosomes, but its exact function has still not been fully unravelled. Mutations were found to be scattered throughout the gene with many of them being private to single families. Correlations have been drawn for the type of mutation rather than for the site of the individual mutation. Virtually all patients carrying two truncating mutations display a severe phenotype with peri- or neonatal demise while surviving patients bear at least one hypomorphic missense mutation. However, about 20–30% of all sibships exhibit major intrafamilial phenotypic variability and it becomes increasingly obvious that ARPKD is clinically and genetically much more heterogeneous and complex than previously thought.

scholarly journals Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease

2020 ◽  
Vol 31 (5) ◽  
pp. 1035-1049 ◽  
Author(s):  
Amandine Viau ◽  
Maroua Baaziz ◽  
Amandine Aka ◽  
Manal Mazloum ◽  
Clément Nguyen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Polycystic Kidneys ◽  
Renal Inflammation ◽  
Tubular Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

BackgroundThe inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression.MethodTo explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1, Stat3, and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines.ResultsOur findings indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1-deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells.ConclusionsSTAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

Human-mouse homologies in the region of the polycystic kidney disease gene (PKD1)

Genomics ◽  
1992 ◽  
Vol 13 (1) ◽  
pp. 35-38 ◽  
Author(s):  
Heinz Himmelbauer ◽  
Marita Pohlschmidt ◽  
Angela Snarey ◽  
Gregory G. Germino ◽  
Debra Weinstat-Saslow ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Disease Gene ◽  
Polycystic Kidney

scholarly journals Adult Inactivation of the Recessive Polycystic Kidney Disease Gene Causes Polycystic Liver Disease

Kidney360 ◽  
2020 ◽  
Vol 1 (10) ◽  
pp. 1066-1074
Author(s):  
Whitney Besse ◽  
Charlotte Roosendaal ◽  
Luigi Tuccillo ◽  
Sounak Ghosh Roy ◽  
Anna-Rachel Gallagher ◽  
...  
Keyword(s):  
Liver Disease ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Disease Gene ◽  
Cyst Formation ◽  
Polycystic Liver Disease ◽  
Polycystic Kidney ◽  
Liver Cysts ◽  
Second Hit ◽  
Polycystic Liver

BackgroundA major difference between autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) lies in the pattern of inheritance, and the resultant timing and focality of cyst formation. In both diseases, cysts form in the kidney and liver as a consequence of the cellular recessive genotype of the respective disease gene, but this occurs by germline inheritance in ARPKD and somatic second hit mutations to the one normal allele in ADPKD. The fibrocystic liver phenotype in ARPKD is attributed to abnormal ductal plate formation because of the absence of PKHD1 expression during embryogenesis and organ development. The finding of polycystic liver disease in a subset of adult PKHD1 heterozygous carriers raises the question of whether somatic second hit mutations in PKHD1 in adults may also result in bile duct-derived cyst formation.MethodsWe used an adult-inducible Pkhd1 mouse model to examine whether Pkhd1 has a functional role in maintaining bile duct homeostasis after normal liver development.ResultsInactivation of Pkhd1 beginning at 4 weeks of age resulted in a polycystic liver phenotype with minimal fibrosis at 17 weeks. Increased biliary epithelium, which lines these liver cysts, was most pronounced in female mice. We assessed genetic interaction of this phenotype with either reduced or increased copies of Pkd1, and found no significant effects on the Pkhd1 phenotype in the liver or kidney from altered Pkd1 expression.ConclusionsSomatic adult inactivation of Pkhd1 results in a polycystic liver phenotype. Pkhd1 is a required gene in adulthood for biliary structural homeostasis independent of Pkd1. This suggests that PKHD1 heterozygous carrier patients can develop liver cysts after somatic mutations in their normal copy of PKHD1.

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