Abnormal Development of Nephrons in &lt;i&gt;Claudin-16&lt;/i&gt;- Defective Japanese Black Cattle

Okada, Kōsuke; Ishikawa, Naoko; Fujimori, K; Goryo, Masanobu; Ikeda, Manabu; Sasaki, Jun; Watanabe, Daisaku; Takasuga, Akiko; Hirano, Takashi; Sugimoto, Yoshikazu

doi:10.1292/jvms.67.171

Cited by 19 publications

(13 citation statements)

References 15 publications

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“…20 Detailed pathoanatomic studies in these cattle characterized an abnormal nephron development with immature glomeruli and tubules. 28 This bovine knockout model suggests that the complete loss of claudin-16 is associated with a severe deterioration of renal function, whereas the heterozygous deletion remains asymptomatic. In humans, no large CLDN16 gene deletions have been identified; however, the recently published work of Hou et al demonstrated for the first time functional differences in vitro among the human CLDN16 missense mutations identified so far.…”

Section: Discussionmentioning

confidence: 98%

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Konrad¹,

Hou

Weber

et al. 2008

Journal of the American Society of Nephrology

118

130

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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by CLDN16 mutations. CLDN16 encodes the renal tight junction protein claudin-16, which is important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle's loop. That FHHNC is frequently associated with progressive renal failure suggests additional roles for claudin-16 in the maintenance of tight junction integrity. An investigation of 32 patients with FHHNC and 17 different mutations was previously reported; here, the analysis is expanded to 39 additional patients and 12 new mutations. Expression studies revealed that five of the 12 new mutations led to partial loss of claudin-16 function and the remaining seven led to complete loss of function. The 23 patients who had mutations resulting in complete loss of function of both alleles were significantly younger at the onset of symptoms than the 46 patients who had at least one mutant allele providing partial function (2.2 versus 5.6 years; P Ͻ 0.01). In addition, those with complete loss of function had a more rapid decline in GFR (7.3 versus 2.9 ml/min per 1.72 m 2 /y; P Ͻ 0.01), leading to 54% requiring renal replacement therapy by age 15 compared with 20% of those with residual function (P Ͻ 0.05). These data suggest that residual function of claudin-16 may delay the progression of renal failure in FHHNC.

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Section: Discussionmentioning

confidence: 98%

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Konrad¹,

Hou

Weber

et al. 2008

Journal of the American Society of Nephrology

118

130

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“…In the first pathologic study of this bovine model, the work by Sasaki et al (17) described lesions classed as "renal tubular dysplasia" with a secondary decrease in the number of nephrons. The work by Okada et al (18) described a decrease in the number of glomeruli with immature tubules, secondary interstitial fibrosis, and lymphocytic infiltration, resulting in abnormal nephron development. Therefore, it has been suggested that defective claudin-16 function disruption may occur very early in the development of tubular tight junctions (2).…”

Section: Discussionmentioning

confidence: 99%

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Godron¹,

Harambat²,

Boccio³

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations.Design, setting, participants, & measurements Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed.Results Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P,0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P,0.01). Treatments seem to have no effect on hypercalciuria and CKD progression.Conclusions Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.

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“…While altered ionic permeability of the paracellular barrier of the reticular lamina due to the absence of claudin-14 is suspected to cause prolonged depolarization and eventual death of outer hairy cells leading to deafness [2], pathogeneses in other diseases, including renal tubular dysplasia in cattle, are unknown. However, pathological findings including tubular atrophy and extensive interstitial nephritis in cattle at ages as young as 2-3 months [12,15] suggest that tubular dysplasia is the primary change, and thus claudin-16 would have some role in developmental formation of renal tubules in addition to selective paracellular transport of divalent cations. Therefore, various approaches are desirable to clarify the roles of claudin-16 in developing kidneys.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of claudin-16 is exclusively restricted to the thick ascending limb (TAL) of Henle's loop, where reabsorption of Mg 2+ and Ca 2+ occurs via the paracellular pathway, in humans [17], mice [8], and cattle (H. Ohta et al, unpublished data), indicating that claudin-16 forms aqueous pores selective to these divalent cations [17]. Interestingly, kidneys from affected animals [12,15] and human patients [21] share some pathological findings such as tubular atrophy and interstitial fibrosis, suggesting that claudin-16 has some pivotal roles in the differentiation and formation of renal tubules in addition to the function in paracelluar transport of Mg 2+ and Ca…”

mentioning

confidence: 99%

Developmental Changes in the Expression of Tight Junction Protein Claudins in Murine Metanephroi and Embryonic Kidneys

Ohta

Adachi

Inaba

2006

The Journal of Veterinary Medical Science

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ABSTRACT. Claudins are the major constituents of tight junction (TJ) strands and participate in the cell-cell adhesion and permeability barrier in epithelial cell layers. To investigate the suitability of metanephroi for analysis of the function of the TJ protein claudins in renal tubular formation, mouse metanephroi from embryos at day 12 of gestation were cultured and expression of claudins was compared with that in embryonic kidneys. During in vitro culture for 8 days, the metanephroi showed expression patterns very similar to those observed in embryonic kidneys in reverse transcription-polymerase chain reaction for the claudins examined, including claudins 1-4, 8, 10, 11, and 16, and the TJ proteins occludin and ZO-1. Immunofluorescence microscopy for claudins 1-4, 8, 10, and 16 showed localization of these claudins at the TJ with occludin and ZO-1 in some restricted tubular segments. These findings indicate that the metanephroi show developmental changes in the expression of the TJ protein claudins, representing those in embryonic kidneys, and thus suggest that the mouse metanephros is suitable to examine the functions of specific claudins in the kidney. KEY WORDS: claudin, metanephroi, mouse, renal tubule, tight junction.The tight junction (TJ) is located at the apicalmost region of the lateral membrane of the epithelial cell, and plays a critical role in sealing the intercellular space in epithelial cellular sheets. The TJ behaves as the primary barrier to the diffusion of solutes and water through the paracellular pathway and maintains cell polarity as a boundary between the apical and basolateral plasma membrane domains [6,16,19,20]. In freeze-fracture replicas of epithelial cells, TJs appear as a continuous anastomosing network of intramembranous particle strands, i.e., TJ strands. The major components of TJ strands are the integral membrane proteins occludin and claudins, and some cytoplasmic scaffolding proteins such as ZO-1 which anchor occludin and claudins to actin filaments [20]. The claudins are a family of more than 20 homologous subtypes which share the same membrane topology and have various tissue-specific and segment-specific distribution patterns [19,20]. Heterogenous claudins form individual TJ strands as heteropolymers to adhere to each other at the cell-cell interface [4] to generate consequential variations in the tightness of individual TJ strands [19].Pathological phenotypes of humans and animals with mutations in genes of specific claudins, including claudins 11 [5], 14 [2,22], and 16 [7,11,17], demonstrate the importance of these TJ proteins in the formation and maintenance of epithelial architecture. However, the precise mechanisms for degeneration of cells and tissues in these diseases remain unknown. CLDN16 gene mutations cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis in the human [17] and renal tubular dysplasia with interstitial nephritis in cattle [7,11] . This putative function of claudin-16 appears to be indispensable and not compensated for by the ...

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Abnormal Development of Nephrons in <i>Claudin-16</i>- Defective Japanese Black Cattle

Cited by 19 publications

References 15 publications

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Developmental Changes in the Expression of Tight Junction Protein Claudins in Murine Metanephroi and Embryonic Kidneys

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