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 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 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.

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 A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease

2010 ◽  
Vol 298 (4) ◽  
pp. F909-F922 ◽  
Author(s):  
Sandra L. Taylor ◽  
Sheila Ganti ◽  
Nikolay O. Bukanov ◽  
Arlene Chapman ◽  
Oliver Fiehn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Human Study ◽  
Cystic Kidney ◽  
Functional Score ◽  
Metabolomic Analysis ◽  
Polycystic Kidney ◽  
Diagnostic Potential

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. Ultrasound is most often used to diagnose ADPKD; such a modality is only useful late in the disease after macroscopic cysts are present. There is accumulating evidence suggesting that there are common cellular and molecular mechanisms responsible for cystogenesis in human and murine PKD regardless of the genes mutated, and, in the case of complex metabolomic analysis, the use of a mouse model has distinct advantages for proof of principle over a human study. Therefore, in this study we utilized a urinary metabolomics-based investigation using gas chromatography-time of flight mass spectrometry to demonstrate that the cystic mouse can be discriminated from its wild-type counterpart by urine analysis alone. At day 26 of life, before there is serological evidence of kidney dysfunction, affected mice are distinguishable by urine metabolomic analysis; this finding persists through 45 days until 64 days, at which time body weight differences confound the results. Using functional score analysis and the KEGG pathway database, we identify several biologically relevant metabolic pathways which are altered very early in this disease, the most highly represented being the purine and galactose metabolism pathways. In addition, we identify several specific candidate biomarkers, including allantoic acid and adenosine, which are augmented in the urine of young cystic mice. These markers and pathway components, once extended to human disease, may prove useful as a noninvasive means of diagnosing cystic kidney diseases and to suggest novel therapeutic approaches. Thus, urine metabolomics has great diagnostic potential for cystic renal disorders and deserves further study.

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.

scholarly journals c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009711
Author(s):  
Abigail O. Smith ◽  
Julie A. Jonassen ◽  
Kenley M. Preval ◽  
Roger J. Davis ◽  
Gregory J. Pazour
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Cyst Formation ◽  
Cystic Kidney Disease ◽  
Nuclear Accumulation ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Jnk Pathway ◽  
Cystic Kidneys

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2. Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.

scholarly journals c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease

2021 ◽  
Author(s):  
Abigail O Smith ◽  
Julie A Jonassen ◽  
Kenley M Preval ◽  
Roger J Davis ◽  
Gregory J. Pazour
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Cyst Formation ◽  
Cystic Kidney Disease ◽  
Nuclear Accumulation ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Jnk Pathway ◽  
Cystic Kidneys

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2 . Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.

scholarly journals Molecular Genetics of Nephronophthisis and Medullary Cystic Kidney Disease

2000 ◽  
Vol 11 (9) ◽  
pp. 1753-1761 ◽  
Author(s):  
FRIEDHELM HILDEBRANDT ◽  
EDGAR OTTO
Keyword(s):  
Kidney Disease ◽  
Focal Adhesion ◽  
Positional Cloning ◽  
Focal Adhesions ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Contact Points ◽  
Medullary Cystic Kidney Disease ◽  
Juvenile Nephronophthisis ◽  
Cyst Development

Abstract.Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) constitute a group of renal cystic diseases that share the macroscopic feature of cyst development at the corticomedullary border of the kidneys. The disease variants also have in common a characteristic renal histologic triad of tubular basement membrane disintegration, tubular atrophy with cyst development, and interstitial cell infiltration with fibrosis. NPH and, in most instances, MCKD lead to chronic renal failure with an onset in the first two decades of life for recessive NPH and onset in adult life for autosomal dominant MCKD. There is extensive genetic heterogeneity with at least three different loci for NPH (NPHP1, NPHP2, andNPHP3) and two different loci for MCKD (MCKD1andMCKD2). Juvenile nephronophthisis, in addition, can be associated with extrarenal organ involvement. As a first step toward understanding the pathogenesis of this disease group, the gene (NPH1) for juvenile nephronophthisis (NPH1) has been identified by positional cloning. Its gene product, nephrocystin, is a novel protein of unknown function that contains asrc-homology 3 domain. It is hypothesized that the pathogenesis of NPH might be related to signaling processes at focal adhesions (the contact points between cells and extracellular matrix) and/or adherens junctions (the contact points between cells). This hypothesis is based on the fact that mostsrc-homology 3-containing proteins are part of focal adhesion signaling complexes, on animal models that exhibit an NPH-like phenotype, and on the recent finding that nephrocystin binds to the protein p130cas, a major mediator of focal adhesion signaling.

scholarly journals Mitochondrial dysfunction and kidney disease

2019 ◽  
Vol 8 (2) ◽  
pp. 18-18
Author(s):  
Sultan Khalid Al Dalbhi ◽  
Fatimah Abdullah Alqarni ◽  
Nawaf Messad Bahatheq ◽  
Reem Saleh Alrasheed ◽  
Rufaydah Ali Alkhowaiter ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Kidney Diseases ◽  
Cystic Kidney Disease ◽  
Renal Tumors ◽  
Cystic Kidney ◽  
Mtdna Mutations ◽  
Focal Segmental Glomerular Sclerosis ◽  
Open Access Journals ◽  
Organ Systems

Context: Mitochondria play a vital role in producing the energy needed for different cellular activities. The role of mitochondria in different diseases and the aging process is gradually being clarified. Different studies have suggested that mitochondrial dysfunction due to mutations in genes that maintain the integrity of mitochondrial DNA (mtDNA), mitophagy, and apoptosis can lead to many neurological and muscular phenotypes as well as diseases in other organ systems including liver, gastrointestinal tract, heart, and kidneys. We examined the current knowledge of mitochondrial dysfunction and its role in renal pathophysiology. Additionally, we examined how chronic kidney diseases can lead to mitochondrial dysfunction through oxidative stress accumulation, which can subsequently lead to other pathological complications. Evidence Acquisitions: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO), and Web of Science have been searched. Results: The renal pathological manifestation of mitochondrial dysfunction includes tubular defects, focal segmental glomerular sclerosis (FSGS), glomerular dysfunction, interstitial nephritis, and cystic kidney disease or renal tumors. These conditions can be caused by mutations in the nuclear genes that are involved in mtDNA replication and transcription or due to mtDNA mutations in the genes involved in the respiratory chain. Conclusions: Clearly, mtDNA plays an important role in renal pathology, and mitochondria may serve as a potential therapeutic target to treat different renal pathologies.

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