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Kidney International Reports Jun 2023
PubMed: 37284675
DOI: 10.1016/j.ekir.2023.04.012 -
Journal of the American Society of... Apr 2023Loss of function of the 2Cl - /H + antiporter ClC-5 in Dent disease causes an unknown impairment in endocytic traffic, leading to tubular proteinuria. The authors...
SIGNIFICANCE STATEMENT
Loss of function of the 2Cl - /H + antiporter ClC-5 in Dent disease causes an unknown impairment in endocytic traffic, leading to tubular proteinuria. The authors integrated data from biochemical and quantitative imaging studies in proximal tubule cells into a mathematical model to determine that loss of ClC-5 impairs endosome acidification and delays early endosome maturation in proximal tubule cells, resulting in reduced megalin recycling, surface expression, and half-life. Studies in a Dent mouse model also revealed subsegment-specific differences in the effects of ClC-5 knockout on proximal tubule subsegments. The approach provides a template to dissect the effects of mutations or perturbations that alter tubular recovery of filtered proteins from the level of individual cells to the entire proximal tubule axis.
BACKGROUND
Loss of function of the 2Cl - /H + antiporter ClC-5 in Dent disease impairs the uptake of filtered proteins by the kidney proximal tubule, resulting in tubular proteinuria. Reduced posttranslational stability of megalin and cubilin, the receptors that bind to and recover filtered proteins, is believed to underlie the tubular defect. How loss of ClC-5 leads to reduced receptor expression remains unknown.
METHODS
We used biochemical and quantitative imaging data to adapt a mathematical model of megalin traffic in ClC-5 knockout and control cells. Studies in ClC-5 knockout mice were performed to describe the effect of ClC-5 knockout on megalin traffic in the S1 segment and along the proximal tubule axis.
RESULTS
The model predicts that ClC-5 knockout cells have reduced rates of exit from early endosomes, resulting in decreased megalin recycling, surface expression, and half-life. Early endosomes had lower [Cl - ] and higher pH. We observed more profound effects in ClC-5 knockout cells expressing the pathogenic ClC-5 E211G mutant. Alterations in the cellular distribution of megalin in ClC-5 knockout mice were consistent with delayed endosome maturation and reduced recycling. Greater reductions in megalin expression were observed in the proximal tubule S2 cells compared with S1, with consequences to the profile of protein retrieval along the proximal tubule axis.
CONCLUSIONS
Delayed early endosome maturation due to impaired acidification and reduced [Cl - ] accumulation is the primary mediator of reduced proximal tubule receptor expression and tubular proteinuria in Dent disease. Rapid endosome maturation in proximal tubule cells is critical for the efficient recovery of filtered proteins.
Topics: Mice; Animals; Low Density Lipoprotein Receptor-Related Protein-2; Dent Disease; Endocytosis; Proteinuria; Endosomes; Kidney Tubules, Proximal; Disease Models, Animal; Mice, Knockout; Cell Culture Techniques; Antiporters
PubMed: 36758125
DOI: 10.1681/ASN.0000000000000084 -
International Journal of Molecular... Jan 2020Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that...
Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.
Topics: Biomarkers; Biopsy; Chloride Channels; DNA Mutational Analysis; Dent Disease; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Kidney Diseases; Mutation; Exome Sequencing
PubMed: 31947599
DOI: 10.3390/ijms21020516 -
World Journal of Pediatrics : WJP Jun 2021Hereditary renal tubular disease can cause hypercalciuria, acid-base imbalance, hypokalemia, hypomagnesemia, rickets, kidney stones, etc. If these diseases are not... (Review)
Review
BACKGROUND
Hereditary renal tubular disease can cause hypercalciuria, acid-base imbalance, hypokalemia, hypomagnesemia, rickets, kidney stones, etc. If these diseases are not diagnosed or treated in time, they can cause kidney damage and electrolyte disturbances, which can be detrimental to the maturation and development of the child. Glomerular involvement in renal tubular disease patients has only been considered recently.
METHODS
We screened 71 papers (including experimental research, clinical research, etc.) about Dent's disease, Gitelman syndrome, and cystinosis from PubMed, and made reference.
RESULTS
Glomerular disease was initially underestimated among the clinical signs of renal tubular disease or was treated merely as a consequence of the tubular damage. Renal tubular diseases affect glomerular podocytes through certain mechanisms resulting in functional damage, morphological changes, and glomerular lesions.
CONCLUSIONS
This article focuses on the progress of changes in glomerular podocyte function in Dent disease, Gitelman syndrome, and cystinosis for the purposes of facilitating clinically accurate diagnosis and scientific treatment and improving prognosis.
Topics: Child; Cystinosis; Gitelman Syndrome; Humans; Kidney Calculi; Kidney Glomerulus; Podocytes
PubMed: 33625696
DOI: 10.1007/s12519-021-00417-0 -
International Journal of Clinical... 2016A case report of a 6-year-old male child who reported with recurrent oral and skin ulcerations since childhood and was diagnosed as lipoid proteinosis manifesting with...
A case report of a 6-year-old male child who reported with recurrent oral and skin ulcerations since childhood and was diagnosed as lipoid proteinosis manifesting with generalized thickening, hardening, and scarring of the skin and hoarseness of voice; is presented here. How to cite this article: Mittal HC, Yadav S, Malik S, Singh G. Lipoid Proteinosis. Int J Clin Pediatr Dent 2016;9(2):149-151.
PubMed: 27365938
DOI: 10.5005/jp-journals-10005-1353 -
International Journal of Clinical... 2016Oral lesions in neonates represent a wide range of diseases often creating apprehension and anxiety among parents. Early examination and prompt diagnosis can aid in... (Review)
Review
Oral lesions in neonates represent a wide range of diseases often creating apprehension and anxiety among parents. Early examination and prompt diagnosis can aid in prudent management and serve as baseline against the future course of the disease. The present review aims to enlist and describe the diagnostic features of commonly encountered oral lesions in neonates. How to cite this article: Patil S, Rao RS, Majumdar B, Jafer M, Maralingannavar M, Sukumaran A. Oral Lesions in Neonates. Int J Clin Pediatr Dent 2016;9(2):131-138.
PubMed: 27365934
DOI: 10.5005/jp-journals-10005-1349 -
British Dental Journal Feb 2021
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Iatrogenic Disease; Vaccination
PubMed: 33637895
DOI: 10.1038/s41415-021-2746-0 -
The American Journal of Dental Science Apr 1890
PubMed: 30749972
DOI: No ID Found -
British Dental Journal Feb 2021
Topics: COVID-19; Delivery of Health Care; Disease Outbreaks; England; Humans; SARS-CoV-2
PubMed: 33637896
DOI: 10.1038/s41415-021-2748-y -
Kidney International Mar 2000Renal stone disease, which affects 12% of males and 5% of females by the seventh decade, occurs as an inherited disorder in 45% of patients and is most commonly... (Review)
Review
Renal stone disease, which affects 12% of males and 5% of females by the seventh decade, occurs as an inherited disorder in 45% of patients and is most commonly associated with hypercalciuria. The biochemical basis for hereditary nephrolithiasis and hypercalciuria is unknown, and this has therefore been investigated by a "positional cloning" approach. As a first step in this approach, the chromosomal locations of two disorders referred to as Dent's disease and X-linked recessive nephrolithiasis (XRN) were determined. These two disorders, which represent unusual forms of the renal Fanconi syndrome, are characterized by a low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and renal failure. An X-linked inheritance for XRN was established by studies of a North American kindred, and a similar inheritance for Dent's disease was indicated by the observation of a greater disease severity in males and an absence of male-to-male transmission in five British families. X-linked polymorphic genetic markers were used in linkage studies of these families, and the genes causing Dent's disease and XRN were mapped to Xp11. In addition, in one family with Dent's disease, a microdeletion involving the DNA probe M27 beta was identified. This microdeletion was further characterized by using yeast artificial chromosomes (YACs) and its size was estimated to be 515 Kb. A search for renal-expressed genes from this region identified a novel gene encoding a chloride channel (CLCN5) with similarities to a family of voltage-gated chloride channels. Molecular genetic studies of CLCN5 demonstrated that mutations, which resulted in a functional loss, were associated with Dent's disease and XRN. In addition, such CLCN5 mutations that would result in a functional loss have also been demonstrated in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis, and an Italian kindred with X-linked recessive hypophosphatemic rickets (XLRH) and hypercalciuria. Thus, four hereditary disorders of nephrolithiasis are due to mutations of the novel chloride channel, CLCN5.
Topics: Amino Acid Sequence; Chloride Channels; Electrophysiology; Genetic Linkage; Humans; Ion Channel Gating; Kidney Calculi; Molecular Sequence Data; Nephrons; Pedigree; Syndrome; X Chromosome
PubMed: 10720930
DOI: 10.1046/j.1523-1755.2000.00916.x