scholarly journals Loss of polycystins suppresses deciliation via the activation of the centrosomal integrity pathway

2020 ◽  
Vol 3 (9) ◽  
pp. e202000750 ◽  
Author(s):  
Vasileios Gerakopoulos ◽  
Peter Ngo ◽  
Leonidas Tsiokas
Keyword(s):  
Cell Cycle ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Cyclic Pattern ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cystic Growth

The primary cilium is a microtubule-based, antenna-like organelle housing several signaling pathways. It follows a cyclic pattern of assembly and deciliation (disassembly and/or shedding), as cells exit and re-enter the cell cycle, respectively. In general, primary cilia loss leads to kidney cystogenesis. However, in animal models of autosomal dominant polycystic kidney disease, a major disease caused by mutations in the polycystin genes (Pkd1 or Pkd2), primary cilia ablation or acceleration of deciliation suppresses cystic growth, whereas deceleration of deciliation enhances cystogenesis. Here, we show that deciliation is delayed in the cystic epithelium of a mouse model of postnatal deletion of Pkd1 and in Pkd1- or Pkd2-null cells in culture. Mechanistic experiments show that PKD1 depletion activates the centrosomal integrity/mitotic surveillance pathway involving 53BP1, USP28, and p53 leading to a delay in deciliation. Reduced deciliation rate causes prolonged activation of cilia-based signaling pathways that could promote cystic growth. Our study links polycystins to cilia dynamics, identifies cellular deciliation downstream of the centrosomal integrity pathway, and helps explain pro-cystic effects of primary cilia in autosomal dominant polycystic kidney disease.

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.

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.

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 Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

2019 ◽  
Author(s):  
Amandine Viau ◽  
Maroua Baziz ◽  
Amandine Aka ◽  
Clément Nguyen ◽  
E. Wolfgang Kuehn ◽  
...  
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

ABSTRACTThe inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results 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, while disrupting 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. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

scholarly journals SP007OLIVE LEAF EXTRACT INHIBITS CELLULAR AND CYSTIC GROWTH IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: AN IN VITRO MODEL

2017 ◽  
Vol 32 (suppl_3) ◽  
pp. iii104-iii104
Author(s):  
Giuseppina Toteda ◽  
Anna Perri ◽  
Donatella Vizza ◽  
Simona Lupinacci ◽  
Antonella La Russa ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Leaf Extract ◽  
In Vitro Model ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Vitro Model ◽  
Cystic Growth

scholarly journals Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

2006 ◽  
Vol 17 (11) ◽  
pp. 3013-3019 ◽  
Author(s):  
Peter C. Harris ◽  
Kyongtae T. Bae ◽  
Sandro Rossetti ◽  
Vicente E. Torres ◽  
Jared J. Grantham ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cystic Growth
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