scholarly journals Nephrocystin-3 is required for ciliary function in zebrafish embryos

2010 ◽  
Vol 299 (1) ◽  
pp. F55-F62 ◽  
Author(s):  
Weibin Zhou ◽  
Julie Dai ◽  
Massimo Attanasio ◽  
Friedhelm Hildebrandt
Keyword(s):  
Kidney Disease ◽  
Positional Cloning ◽  
Primary Cilia ◽  
Kidney Diseases ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Zebrafish Embryos ◽  
Convergent Extension ◽  
Renal Cystic Disease ◽  
Ciliary Function

Nephronophthisis (NPHP) is the most frequent genetic cause of end-stage renal failure in the first three decades of life. It is characterized primarily by renal cysts with extrarenal involvements of the eye and brain. Ten recessive genes responsible for NPHP have been identified by positional cloning. This discovery supported a unifying theory of renal cystic disease, which states that all proteins mutated in cystic kidney diseases of human, mice, or zebrafish are expressed in primary cilia of renal epithelial cells. Mutations in nephrocystin-3 (NPHP3) are the cause of human nephronophthisis type 3 and polycystic kidney disease (pcy) mouse mutants. To study the functional role of NPHP3 in normal embryonic development and in the pathogenesis of cystic kidney disease, we characterized the zebrafish ortholog nphp3 by morpholino oligo (MO)-mediated knockdown. When nphp3 function was suppressed by either of the two MOs blocking the translation of the protein or the splicing of mRNA, zebrafish embryos displayed hydrocephalus and pronephric cysts. Knockdown of nphp3 also led to situs inversus phenotypes due to defective cilia at Kupffer's vesicle. We showed that nphp3 genetically interacts with nphp2/inversin and human NPHP3 localizes to primary cilia in Madin-Darby canine kidney cells. Like nphp2/inversin, nphp3 knockdown affected morphogenic cell movement during gastrulation, suggesting nphp3 is essential to regulate convergent extension. Thus nphp3, cooperating with nphp2/inversin, plays an essential role related to ciliary function, and the knockdown provides an animal model that may be used for studies of the pathogenesis and therapy for this disease.

scholarly journals Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1762
Author(s):  
Shabarni Gupta ◽  
Justyna E. Ozimek-Kulik ◽  
Jacqueline Kathleen Phillips
Keyword(s):  
Kidney Disease ◽  
Positional Cloning ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Diverse Range ◽  
Therapeutic Modalities ◽  
Molecular Features ◽  
Next Generation Sequencing Ngs

The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients.

scholarly journals Autosomal recessive polycystic kidney disease and complex nephronophtisis medullary cystic disease

2008 ◽  
Vol 136 (Suppl. 4) ◽  
pp. 348-352
Author(s):  
Emilija Golubovic
Keyword(s):  
Kidney Disease ◽  
Mammalian Cells ◽  
Autosomal Recessive ◽  
Primary Cilia ◽  
Calcium Influx ◽  
Control Cell ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Cystic Disease ◽  
Renal Cystic Disease

Reseach during the past decade has led to the discovery that defects in some proteins that localize to primary cilia or the basal body are the main contributors to renal cyst development. Autosomal recessive polycystic disease and nephronophthisis-medullary cystic kidney disease are named ciliopathies. The cilium is a microtubule-based organelle that is found on most mammalian cells. Cilia-mediated hypothesis has evolved into the concept of cystogenesis, cilia bend by fluid initiate a calcium influx that prevents cyst formation. Cilia might sense stimuli in the cell enviroment and control cell polarity and mitosis. A new set of pathogenic mechanisms in renal cystic disease defined new therapeutic targets, control of intracellular calcium, inhibition of cAMP and down regulation cannonical Wnt signaling.

scholarly journals Towards Modelling Genetic Kidney Diseases with Human Pluripotent Stem Cells

Nephron ◽  
2021 ◽  
pp. 1-12
Author(s):  
Kirsty M. Rooney ◽  
Adrian S. Woolf ◽  
Susan J. Kimber
Keyword(s):  
Stem Cell ◽  
Kidney Disease ◽  
Cell Biology ◽  
Kidney Diseases ◽  
Premature Mortality ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Metanephric Mesenchyme ◽  
Potential Therapeutic Application ◽  
Made In

<b><i>Background:</i></b> Kidney disease causes major suffering and premature mortality worldwide. With no cure for kidney failure currently available, and with limited options for treatment, there is an urgent need to develop effective pharmaceutical interventions to slow or prevent kidney disease progression. <b><i>Summary:</i></b> In this review, we consider the feasibility of using human pluripotent stem cell-derived kidney tissues, or organoids, to model genetic kidney disease. Notable successes have been made in modelling genetic tubular diseases (e.g., cystinosis), polycystic kidney disease, and medullary cystic kidney disease. Organoid models have also been used to test novel therapies that ameliorate aberrant cell biology. Some progress has been made in modelling congenital glomerular disease, even though glomeruli within organoids are developmentally immature. Less progress has been made in modelling structural kidney malformations, perhaps because sufficiently mature metanephric mesenchyme-derived nephrons, ureteric bud-derived branching collecting ducts, and a prominent stromal cell population are not generated together within a single protocol. <b><i>Key Messages:</i></b> We predict that the field will advance significantly if organoids can be generated with a full complement of cell lineages and with kidney components displaying key physiological functions, such as glomerular filtration. The future economic upscaling of reproducible organoid generation will facilitate more widespread research applications, including the potential therapeutic application of these stem cell-based technologies.

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.

A Sphingosine-1-Phosphate Modulator Ameliorates Polycystic Kidney Disease in Han:SPRD Rats

2019 ◽  
Vol 51 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Xin Li ◽  
Ming Wu ◽  
Limin Chen ◽  
Junyan Lu ◽  
Guo Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Kidney Diseases ◽  
Cordyceps Sinensis ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Sphingosine 1 Phosphate

Background: Inflammation plays an important role in polycystic kidney disease (PKD). Cordyceps sinensis, a prized ­Chinese medicinal herb, exerts anti-tumor, anti-inflammatory and anti-metastatic effects and benefits patients with kidney diseases. The aim of this study was to test the efficacy of FTY720, an immunosuppressant derived from C. sinensis, in a rat cystic kidney disease model, and explore its underlining mechanism. Methods: Male wild type and Cy/+ Han:SPRD rats were treated with FTY720 at 3 and 10 mg/kg/day for 5 weeks and 12 weeks by gavage. Blood and kidney were collected for functional, morphological, RNA, and protein analysis. Results: Inflammation is activated in Cy/+ Han:SPRD rats. Inflammatory cytokines including interleukin 6 and tumor necrosis factor alpha were upregulated and inflammation-related pathways were activated, such as nuclear factor κB and signal transducer and activator of transcription 3 (STAT3) pathways. Furthermore, the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), a regulator of inflammation, was accumulated in the Cy/+ Han:SPRD rats. FTY720 significantly reduced cyst growth and delayed disease progression by reducing the accumulation of S1P, thereby inhibiting inflammatory responses. Conclusion: FTY720 treatment reduced the expression of inflammatory cytokines and attenuated the activation of NK-κB and STAT3 pathways in Cy/+ Han:SPRD rats. It suggests that FTY720 may serve as a therapeutic agent for clinical autosomal dominant PKD treatment.

scholarly journals Multiomic identification of factors associated with progression to cystic kidney disease in mice with nephron Ift88 disruption

2021 ◽  
Author(s):  
Chunyan Hu ◽  
Katherine Beebe ◽  
Edgar J Hernandez ◽  
Jose M Lazaro-Guevara ◽  
Monica P Revelo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Kidney Disease ◽  
Primary Cilia ◽  
Gene Mutations ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Factors Associated ◽  
Lipidomic Analysis ◽  
Renal Histology ◽  
Chain Acyl

Ift88 gene mutations cause primary cilia loss and polycystic kidney disease (PKD) in mice. Nephron Ift88 knockout (KO) at 2 months postnatal does not affect renal histology at 4 months postnatal and causes PKD only in males by 11 months postnatal. To identify factors associated with PKD development, kidneys from 4-month-old male and female control and Ift88 KO mice underwent transcriptomic, proteomic, western, metabolomic and lipidomic analysis. mRNAs involved in extracellular matrix (ECM) synthesis and degradation were selectively upregulated in male KO mice. Proteomic analysis was insufficiently sensitive to detect most ECM components, while western analysis paradoxically revealed reduced fibronectin and collagen I in male KO mice. Only male KO mice upregulated mRNAs encoding fibrinogen subunits and receptors for VEGF and PDGF; Per2, Per3 and Nrld2 clock mRNAs were selectively decreased in male KO mice. Proteomic, metabolomic and lipidomic analysis detected a relative (vs same sex control) decrease in factors involved in fatty acid ß-oxidation in female KO, while increased or unchanged levels in male KO, mice including medium chain acyl-CoA dehydrogenase, 3-hydroxybutyrate, and acylcarnitine. Three putative mRNA biomarkers of cystogenesis in male Ift88 KO mice (similar control levels between sexes and uniquely altered by KO in males) were identified, including high levels (Fga and Sdf2l1) and low levels (Banp) in male KO mice. These findings suggest that relative alterations in renal ECM metabolism, fatty acid ß-oxidation, and other pathways precede cystogenesis in Ift88 KO mice. In addition, potential novel biomarkers of cystogenesis in Ift88 KO mice have been identified.

scholarly journals Notch signaling regulates Akap12 expression and primary cilia length during renal tubule morphogenesis

2019 ◽  
Author(s):  
Malini Mukherjee ◽  
Ishara Ratnayake ◽  
Madhusudhana Janga ◽  
Eric Fogarty ◽  
Shania Scheidt ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Notch Signaling ◽  
Primary Cilia ◽  
Renal Tubule ◽  
Ectopic Expression ◽  
Clinical Manifestations ◽  
Alagille Syndrome ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Cystic Kidneys

AbstractAlagille syndrome patients present with loss of function mutations in either JAG1 or NOTCH2. About 40-50% of patients have kidney abnormalities, with multi-cystic, dysplastic kidneys being one of the more frequent kidney defects. Additionally, gain-of-function mutations in NOTCH2 are associated with cystic kidneys in Hajdu-Cheney syndrome patients. Conditional inactivation of Notch1, Notch2, or RBPJ within the nephrogenic lineage impairs nephrogenesis and produces proximal tubule cysts in mice. How perturbations in Notch signaling cause renal tubular cysts remains unclear. Here we have determined that inhibition of Notch signaling in the kidney increases Akap12 expression. Ectopic expression of Akap12 in renal epithelia results in abnormally long primary cilia similar to those observed in Notch-signal-deficiency. Both loss of Notch signaling and elevated Akap12 expression disrupt the ability of renal epithelial cells to form spherical structures with a single lumen when grown embedded in matrix. We conclude that Notch signaling regulates Akap12 expression to ensure normal primary cilia length and renal epithelial morphogenesis, and suggest that diseases associated with defective Notch signaling, such as Alagille syndrome, maybe mechanistically related to ciliopathies.Translational StatementThe current study examines how a reduction in Notch signaling results in abnormal renal tubule formation, as occurs in Alagille Syndrome patients with mutations in JAG1 or NOTCH2. The finding that reduced Notch signaling results in abnormally long cilia is suggestive that some of the clinical manifestations in Alagille Syndrome, such as small cystic kidneys, may originate due to defective cilia function. Linking Notch to primary cilia also opens up the possibility that coinheritance of mutations in ciliopathy genes along with a mutation in JAG1 or NOTCH2 may enhance the severity of the clinical phenotypes such as cystic kidney disease and may explain the variable occurrence and onset of kidney disease among Alagille Syndrome patients.

scholarly journals Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease

2022 ◽  
Vol 23 (2) ◽  
pp. 884
Author(s):  
Sonja Djudjaj ◽  
Panagiotis Kavvadas ◽  
Niki Prakoura ◽  
Roman D. Bülow ◽  
Tiffany Migeon ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Notch Signaling ◽  
Kidney Diseases ◽  
Genetic Disorder ◽  
Renal Cysts ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Renal Tubules ◽  
Renal Tubular Cells ◽  
Stage Renal Disease

Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions.

scholarly journals Reverse Phenotyping Maternal Cystic Kidney Disease by Diagnosis in a Newborn: Case Report and Literature Review on Neonatal Cystic Kidney Diseases

2021 ◽  
Vol 28 (2) ◽  
pp. 5
Author(s):  
Dovilė Ruzgienė ◽  
Meda Sutkevičiūtė ◽  
Birutė Burnytė ◽  
Kristina Grigalionienė ◽  
Augustina Jankauskienė
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Pediatric Population ◽  
Genetic Disorders ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Kidney Cysts ◽  
Fetal Malformations

Kidney cysts are the most common kidney lesion, while congenital kidney cysts are mostly found in pediatric population. Neonatal kidney cysts can develop due to fetal malformations, rare genetic disorders or can be acquired which is very rare. Kidney cysts may be the only isolated finding or be part of the overall phenotype. They can be asymptomatic, found by ultrasound accidentally or can manifest from mild to life-threatening symptoms. Therefore, early diagnosis is very important. Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the most common causes of kidney cysts in the neonatal population. This review highlights the most common kidney cystic diseases during the neonatal period and a rare clinical case of HNF1B-associated disease.

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