A Homozygous Dab1−/− Is a Potential Novel Cause of Autosomal Recessive Congenital Anomalies of the Mice Kidney and Urinary Tract

This study aimed to explore morphology changes in the kidneys of Dab1−/− (yotari) mice, as well as expression patterns of reelin, NOTCH2, LC3B, and cleaved caspase3 (CASP3) proteins, as potential determinants of normal kidney formation and function. We assumed that Dab1 functional inactivation may cause disorder in a wide spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Animals were sacrificed at postnatal days P4, P11, and P14. Paraffin-embedded kidney tissues were sectioned and analyzed by immunohistochemistry using specific antibodies. Kidney specimens were examined by bright-field, fluorescence, and electron microscopy. Data were analyzed by two-way ANOVA and t-tests. We noticed that yotari kidneys were smaller in size with a reduced diameter of nephron segments and thinner cortex. TEM microphotographs revealed foot process effacement in the glomeruli (G) of yotari mice, whereas aberrations in the structure of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) were not observed. A significant increase in reelin expression, NOTCH2, LC3B and cleaved CASP3 proteins was observed in the glomeruli of yotari mice. Renal hypoplasia in conjunction with foot process effacement and elevation in the expression of examined proteins in the glomeruli revealed CAKUT phenotype and loss of functional kidney tissue of yotari.

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Deletion in the Cobalamin Synthetase W Domain–Containing Protein 1 Gene Is associated with Congenital Anomalies of the Kidney and Urinary Tract

Journal of the American Society of Nephrology ◽

10.1681/asn.2019040398 ◽

2019 ◽

Vol 31 (1) ◽

pp. 139-147

Author(s):

Shoichiro Kanda ◽

Masaki Ohmuraya ◽

Hiroyuki Akagawa ◽

Shigeru Horita ◽

Yasuhiro Yoshida ◽

...

Keyword(s):

Urinary Tract ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Congenital Anomalies ◽

Kidney Development ◽

Family Members ◽

Incomplete Penetrance ◽

Whole Genome ◽

Renal Hypoplasia ◽

Unilateral Renal Agenesis

BackgroundResearchers have identified about 40 genes with mutations that result in the most common cause of CKD in children, congenital anomalies of the kidney and urinary tract (CAKUT), but approximately 85% of patients with CAKUT lack mutations in these genes. The anomalies that comprise CAKUT are clinically heterogenous, and thought to be caused by disturbances at different points in kidney development. However, identification of novel CAKUT-causing genes remains difficult because of their variable expressivity, incomplete penetrance, and heterogeneity.MethodsWe investigated two generations of a family that included two siblings with CAKUT. Although the parents and another child were healthy, the two affected siblings presented the same manifestations, unilateral renal agenesis and contralateral renal hypoplasia. To search for a novel causative gene of CAKUT, we performed whole-exome and whole-genome sequencing of DNA from the family members. We also generated two lines of genetically modified mice with a gene deletion present only in the affected siblings, and performed immunohistochemical and phenotypic analyses of these mice.ResultsWe found that the affected siblings, but not healthy family members, had a homozygous deletion in the Cobalamin Synthetase W Domain–Containing Protein 1 (CBWD1) gene. Whole-genome sequencing uncovered genomic breakpoints, which involved exon 1 of CBWD1, harboring the initiating codon. Immunohistochemical analysis revealed high expression of Cbwd1 in the nuclei of the ureteric bud cells in the developing kidneys. Cbwd1-deficient mice showed CAKUT phenotypes, including hydronephrosis, hydroureters, and duplicated ureters.ConclusionsThe identification of a deletion in CBWD1 gene in two siblings with CAKUT implies a role for CBWD1 in the etiology of some cases of CAKUT.

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Urinary System Birth Defects in Surgically Treated Infants in Sarajevo Region of Bosnia and Herzegovina

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2008.2965 ◽

2008 ◽

Vol 8 (2) ◽

pp. 126-130

Author(s):

Selma Aličelebić ◽

Dina Kapić ◽

Zakira Mornjaković

Keyword(s):

Urinary Tract ◽

Vesicoureteral Reflux ◽

Bosnia And Herzegovina ◽

Congenital Anomalies ◽

Prune Belly Syndrome ◽

Urinary System ◽

Renal Hypoplasia ◽

Female Patients ◽

Clinical Records ◽

Urinary Tract Anomalies

Congenital anomalies of the urinary system are relatively common anomalies. In Bosnia and Herzegovina there is no existent unique evidence of congenital anomalies and registries. The aim of this study was to obtain the frequency of different urinary tract anomalies types and their sex distribution among cases hospitalized in the Department of Pediatric Surgery of the University of Sarajevo Clinics Centre, Bosnia and Herzegovina, during the period from January 2002 to December 2006. Retrospective study was carried out on the basis of clinical records. Standard methods of descriptive statistics were performed for the data analysis. Among 289 patients that were surgically treated 62,37% of the patients were male patients, while 37,63% were female patients. Twenty nine different urinary system anomalies types were found in this study. These were: vesicoureteral reflux (99 cases or 30,75%), hypospadias (62 cases or 19,26%), pelviureteric junction obstruction (42 cases or 13,04%), megaureter (35 cases or 10,87%), duplex pelvis and ureter (16 cases or 4,97%), bladder diverticulum (8 cases or 2,48%), ureterocoele (7 cases or 2,17%), stenosis of the external urethral opening (6 cases or 1,86%), ectopic kidney, duplex kidney and pelvis (each 5 cases or 1,55%), polycystic kidneys and urethral stricture (each 4 cases or 1,24%), multicystic kidney (3 cases or 0,93%), kidney agenesis, ureter agenesis, urethral diverticulum, ectopic ureter, horseshoe kidney and fetal kidney (each 2 cases or 0,62%), renal aplasia, urethral atresia, renal cyst, urachal cyst, epispadias, bladder exstrophy, renal hypoplasia, renal malrotation and Prune-Belly syndrome (each 1 case or 0,31%). According to this study, urinary tract anomalies were more common in male than in female patients (62,37%), Generally, the most frequent anomaly type was vesicoureteral reflux in total number of 99 cases, and in females (66 cases), but hypospadias was the most common anomaly in males (62 cases). The anomalies of other systems associated with urinary system anomalies were found in ten cases. These were: cryptorchidism, congenital inguinal hernia, open inner inguinal ring, uterus bicornis unicollis and one case of multiple anomalies.

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Angiotensin II Type 2 Receptor Gene Polymorphism in Caucasian Children With a Wide Spectrum of Congenital Anomalies of the Kidney and Urinary Tract

Pediatric Research ◽

10.1203/pdr.0b013e3180679101 ◽

2007 ◽

Vol 62 (1) ◽

pp. 83-87 ◽

Cited By ~ 5

Author(s):

Ekaterini Siomou ◽

Ioanna Bouba ◽

Konstantinos D Kollios ◽

Frederica Papadopoulou ◽

Maria Syrrou ◽

...

Keyword(s):

Urinary Tract ◽

Angiotensin Ii ◽

Gene Polymorphism ◽

Congenital Anomalies ◽

Wide Spectrum ◽

Receptor Gene ◽

Receptor Gene Polymorphism

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Tangeretin Ameliorates Podocyte Injury Through Blocking Epithelial to Mesenchymal Transition in High Glucose-exposed Podocytes and Diabetic Kidneys (P06-009-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-009-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Min-Kyung Kang ◽

Young-Hee Kang

Keyword(s):

Epithelial Cells ◽

High Glucose ◽

Epithelial To Mesenchymal Transition ◽

Kidney Tissue ◽

Slit Diaphragm ◽

Podocyte Injury ◽

Mesenchymal Transition ◽

Tissue Sections ◽

Foot Process Effacement ◽

Foot Process

Abstract Objectives Epithelial to mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties. This process contributes to the accumulation of matrix proteins in kidney and leads to renal glomeruli fibrosis. Tangeretin is an O-polymethoxylated flavone with anti-inflammatory and antioxidant properties that is found in citrus peels. This study investigated the renoprotective effects of tangeretin on EMT-mediated podocyte injury and fibrosis caused by hyperglycemia. Methods Mouse glomerular epithelial cells (podocyte) were incubated in media containing 5.5 mM glucose, 27.5 mM mannitol as an osmotic control or 33 mM glucose (high glucose) in the absence and presence of 1–20 μM tangeretin for up to 4 days. Antibodies of E-cadherin, N-cadherin, α-SMA, nephrin, podocin, P-cadherin and collagen1 were used for Western blotting. The in vivo animal model employed db/db mice orally administrated with 10 mg/kg tangeretin for 8 weeks. Kidney tissue extracts of were Western-blotted, and tissue sections cut down in 5 µM thickness were immunohistochemically stained. In addition, kidney tissue sections (ultrathin sections, 70 nm) were observed with transmission electron microscopy (TEM). Results Non-toxic tangeretin enhanced expression of the podocyte slit diaphragm proteins of nephrin, podocin and P-cadherin down-regulated by glucose stimulation. Also, tangeretin inhibited high glucose-induced expression of the mesenchymal markers of N-cadherin and α-smooth muscle actin, whereas the induction of the epithelial marker E-cadherin was enhanced. Furthermore tangeretin attenuated the fibronectin induction and collagen production elevated by the presence of high glucose. The TEM images revealed that podocyte foot process effacement occurred in diabetic mouse glomeruli. However, oral administration of 10 mg/kg tangeretin reduced urine albumin excretion and improved foot process effacement of diabetic podocytes through inhibiting loss of glomerular slit junction proteins. Conclusions These results demonstrated that tangeretin maintained the structures of podocyte slit diaphragm in a robust form, and inhibited podocyte injury through blocking epithelial to mesenchymal transition of podocytes. Therefore, tangeretin may be a potent renoprotective agent counteracting diabetes-associated loss of podocyte slit diaphragm and maintaining glomerular filtration barrier. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MEST) (NRF-2017R1A6A3A04011473).

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