Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney 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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New PAX2 Mutation Associated with Polycystic Kidney Disease: A Case Report

Clinical Medicine Insights Pediatrics ◽

10.1177/1179556521992354 ◽

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.

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Uncontrolled hypertension and hyperreninemia after hemorrhage in a patient with end-stage renal disease and acquired renal cysts.

Journal of the American Society of Nephrology ◽

10.1681/asn.v5122 ◽

1994 ◽

Vol 5 (1) ◽

pp. 22-26

Author(s):

S Bongu ◽

P F Faubert ◽

J G Porush ◽

F Gulmi

Keyword(s):

Kidney Disease ◽

Esrd Patient ◽

Renal Cysts ◽

Cystic Kidney Disease ◽

Uncontrolled Hypertension ◽

Cystic Kidney ◽

First Case ◽

Acquired Cystic Kidney Disease ◽

Perinephric Hematoma ◽

Stage Renal Disease

Acquired cystic kidney disease occurs in over 74% of patients with ESRD on hemodialysis for more than 4 yr. A variety of complications have been associated with these cysts including bleeding, lithiasis, infection, obstruction, and malignant transformation. An ESRD patient who developed accelerating hypertension secondary to an acute perinephric hematoma due to a bleeding-acquired renal cyst is described. The hypertension, which was refractory to aggressive drug therapy, was controlled only after the involved kidney was removed, after the demonstration of an elevated ipsilateral renal vein renin level. This is the first case reported in which worsening hypertension, apparently due to the "Page Kidney," developed as a complication of perinephric bleeding in an ESRD patient with acquired cystic kidney disease.

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Phthalate Esters, Cystic Kidney Disease in Animals and Possible Effects on Human Health: A Review

Human & Experimental Toxicology ◽

10.1177/096032719000900607 ◽

1990 ◽

Vol 9 (6) ◽

pp. 397-401 ◽

Cited By ~ 17

Author(s):

K.N. Woodward

Keyword(s):

Kidney Disease ◽

Human Health ◽

Phthalate Esters ◽

Renal Cysts ◽

Cystic Kidney Disease ◽

Cystic Kidney ◽

Peroxisome Proliferation ◽

Peroxisome Proliferators ◽

Prolonged Administration ◽

Route Of Exposure

1 Phthalate esters are known to cause hepatic peroxisome proliferation in rodents and, after prolonged administration, hepatocarcinogenesis. Peroxisome proliferators as a group are hepatocarcinogenic. The mechanism is not known but it does not appear to involve a direct genotoxic element. 2 DEHP and DBP have been shown to cause renal cysts in rodents and they also produce renal peroxisome proliferation. There are no data to causally link the two phenomena. 3 Although renal cysts have been noted in haemodialysis patients and haemodialysis is a route of exposure to DEHP, there are no data to suggest a cause and effect relationship. 4 More studies are needed on the mechanism of renal cystogenesis.

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Towards Modelling Genetic Kidney Diseases with Human Pluripotent Stem Cells

Nephron ◽

10.1159/000514018 ◽

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

Background: 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. Summary: 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. Key Messages: 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.

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Molecular genetics of renal ciliopathies

Biochemical Society Transactions ◽

10.1042/bst20200791 ◽

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.

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

American Journal of Nephrology ◽

10.1159/000502855 ◽

2019 ◽

Vol 51 (1) ◽

pp. 1-10 ◽

Cited By ~ 1

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.

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Prevalence of primary renal diseases among patients on maintenance haemodialysis: a hospital based study

KYAMC Journal ◽

10.3329/kyamcj.v2i2.13262 ◽

2013 ◽

Vol 2 (2) ◽

pp. 182-186

Author(s):

ST Ahmed ◽

MA Rahim ◽

Z Ali ◽

MM Iqbal

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

End Stage Renal Disease ◽

Cystic Kidney Disease ◽

Cystic Kidney ◽

Renal Diseases ◽

Socioeconomic Condition ◽

Co Morbidity ◽

Stage Renal Disease ◽

End Stage

Background: Chronic Kidney Disease (CKD) is the third most common non-communicable disease throughout the world. Studies have shown that kidney patients suffer much from hypertension, diabetes than glomerulonephritis. Many of these CKD patients ultimately terminate to End Stage Renal Disease (ESRD) when life is not sustainable unless hemodialysis is initiated. Aim: The aim of this study was to identify primary renal disease leading to ESRD requiring hemodialysis and associated co-morbidities. Material and methods: Data was collected purposively from selected six hemodialysis centers. Patients were selected purposively who were available at the time of interview. Data was collected on working days at three shifts After taking informed consent from patients the pre-tested questionnaire was filled up by taking general history, family history, socioeconomic condition, drug history and available records were reviewed for collecting previous biochemical parameters. All entered data were analyzed by using SPSS program version 13.0. Result: Among total 393 subjects, male was 247(63%) and female 146 (37%). Majority were middle aged. Glomerulonephritis were found to be the leading cause of End Stage Renal Disease (ESRD) (50.4%), followed by diabetes in 31.1%, Poly Cystic Kidney Disease (PKD) 5.3%, Renal Stone in 3.7% and rest other. Among the study population hypertension was the most common co morbidity disease (63%) followed by ischemic heart disease and Cerebrovascular accidents. Conclusion: Glomerulonephritis was found to be the leading cause of End Stage Renal Disease (ESRD) and diabetic nephropathy was the second common cause. Hypertension was the most common associated co morbid disease. To evaluate the actual disease pattern a large scale study is required to find the outcome of haemodialysis patients.DOI: http://dx.doi.org/10.3329/kyamcj.v2i2.13262KYAMC Journal Vol.2(2) January 2012, 182-186

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Cystic Kidney Diseases

Kidney Protection ◽

10.1093/med/9780190611620.003.0038 ◽

2019 ◽

pp. 373-388

Author(s):

Fouad T. Chebib ◽

Vicente E. Torres

Keyword(s):

Kidney Disease ◽

Kidney Diseases ◽

Average Rate ◽

Cystic Kidney ◽

Renal Protection ◽

Clinical Complications ◽

Kidney Cysts ◽

Autosomal Dominant Polycystic Kidney ◽

Stage Renal Disease ◽

End Stage

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease, is characterized by relentless development of kidney cysts, hypertension, and eventually end-stage renal disease. The enlargement of the bilateral kidney cysts is gradual throughout the lifetime of the patient until little renal parenchyma is recognizable. At that stage, the average rate of GFR decline is 4.4 to 5.9 mL/min/year. Over the past few years, several advancements in diagnosing, prognosticating, and understanding the pathogenesis of the disease have been made. The natural course of ADPKD makes it an ideal disease to be targeted for renal protection. This chapter discusses various aspects of pathophysiology and molecular pathways and addresses in details the various pharmaceutical and nonpharmaceutical interventions in the journey of prevention of clinical complications of ADPKD.

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Nephrocystin-3 is required for ciliary function in zebrafish embryos

AJP Renal Physiology ◽

10.1152/ajprenal.00043.2010 ◽

2010 ◽

Vol 299 (1) ◽

pp. F55-F62 ◽

Cited By ~ 39

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.

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