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 New PAX2 Mutation Associated with Polycystic Kidney Disease: A Case Report

2021 ◽  
Vol 15 ◽  
pp. 117955652199235
Author(s):  
Jessica Maria Forero-Delgadillo ◽  
Vanessa Ochoa ◽  
Natalia Duque ◽  
Jaime Manuel Restrepo ◽  
Hernando Londoño ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Renal Cysts ◽  
Renal Dysplasia ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Incomplete Penetrance ◽  
Wide Range ◽  
Stage Renal Disease

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage renal disease in children. Diagnosis by genetic testing has proven challenging due to its genetic and phenotypic heterogeneity, as well as incomplete penetrance. We report a case on a 16-months old female with a history of renal cysts and a PAX2 mutation. Case presentation: The patient presented with a prenatal diagnosis of Potter sequence and a postnatal diagnosis of renal cysts. An ultrasound at 20 weeks gestation revealed right renal agenesis and possible left renal dysplasia. Post natal genetic analyses identified a novel mutation in PAX2. Conclusion: Cystic kidney disease is often underdiagnosed due to its variable expressivity and wide range of clinical manifestations; PAX2 genetic screening should be considered for all patients with CAKUT.

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.

scholarly journals Nephronophthisis and medullary cystic kidney disease complex

2005 ◽  
Vol 62 (9) ◽  
pp. 683-688
Author(s):  
Marijana Stanisic ◽  
Rajko Hrvacevic ◽  
Zoran Paunic ◽  
Stanko Petrovic
Keyword(s):  
Renal Failure ◽  
Kidney Disease ◽  
Ultrasound Examination ◽  
Clinical Manifestations ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Laboratory Findings ◽  
Disease Complex ◽  
Terminal Renal Failure ◽  
Medullary Cystic Kidney Disease

Background. Nephronophthisis and medullary cystic kidney disease complex refers to the genetic heterogeneous group of inherited tubulointerstital nephritis. Nephronophthisis comprises at last 3 clinical manifestations, has the autosomal recessive pattern of inheritance, appears early in life and is the most frequent inherited kidney disease that causes terminal renal failure in childhood, while medullary cystic kidney disease has the autosomal dominant pattern of inheritance, is less frequent, and terminal renal failure appears later in life. These two forms have similar clinical and morphological findings but extrarenal manifestations, the median ages of occurrence of terminal renal failure, and siblings presence help us distinguish these diseases. Case report. In this article we illustrated the case of a 20- years old patient with the suspicion of having complex nephornophthisis and medullary cystic kidney disease based upon mild renal failure, seen in routinely taken laboratory findings and bilateral cysts in corticomedullary region of the kidneys verified on abdominal ultrasound examination. Conclusion. This disease should rise suspicion in children or adolescents with progressive renal failure, a typical clinical manifestation, blood and urine samples results, bilateral cysts in the corticomedullary region of the kidneys seen during ultrasound examination of the kidneys and family inheritance.

scholarly journals CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease

2020 ◽  
Author(s):  
Maike Getwan ◽  
Anselm Hoppmann ◽  
Pascal Schlosser ◽  
Kelli Grand ◽  
Weiting Song ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Disease Genes ◽  
Cystic Kidneys ◽  
Jeune Syndrome ◽  
Limb Deformities ◽  
Organ Manifestations ◽  
Short Rib Polydactyly Syndrome ◽  
Sensenbrenner Syndrome

AbstractSkeletal ciliopathies (e.g. Jeune syndrome, short rib polydactyly syndrome, Sensenbrenner syndrome) are frequently associated with cystic kidney disease and other organ manifestations, but a common molecular mechanism has remained elusive.We established two models for skeletal ciliopathies (ift80 and ift172) in Xenopus tropicalis, which exhibited severe limb deformities, polydactyly, cystic kidneys, and ciliogenesis defects, closely matching the phenotype of affected patients.Employing data-mining and an in silico screen we identified candidate genes with similar molecular properties to genetically validated skeletal ciliopathy genes. Among four genes experimentally validated, CRISPR/Cas9 targeting of ttc30a replicated all aspects of the phenotypes observed in the models of genetically confirmed disease genes, including ciliary defects, limb deformations and cystic kidney disease.Our findings establish three new models for skeletal ciliopathies (ift80, ift172, ttc30a) and identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins implicating post-translational tubulin modifications in its pathogenesis.

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 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 Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease

2021 ◽  
Vol 118 (39) ◽  
pp. e2106770118
Author(s):  
Maike Getwan ◽  
Anselm Hoppmann ◽  
Pascal Schlosser ◽  
Kelli Grand ◽  
Weiting Song ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Cysts ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Cartilage Defects ◽  
Disease Genes ◽  
Embryonic Mouse ◽  
Cystic Kidneys ◽  
Jeune Syndrome ◽  
Sensenbrenner Syndrome

Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci (ift80 and ift172) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Xenopus tropicalis. Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining–based in silico screen found ttc30a to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. Ttc30a/b transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type–specific manner. These findings have implications for potential therapeutic strategies.

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.

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