Autosomal dominant tubulointerstitial kidney disease: a new tool to guide genetic testing

LaFavers, Kaice A.; El-Achkar, Tarek M.

doi:10.1016/j.kint.2020.05.046

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…When we analyzed the list of genes altered by CLCN5 silencing, we found that among the most down-regulated genes there were genes that could be relevant to understand the pathophysiology of DD1, at the proximal tubule level. Such an examples are secretory leukocyte peptidase inhibitor ( SLPI ; logFC -5.01), which has been related to PTCs regeneration ( 36 ), MUC1 (Mucin1; logFC -4.72), whose mutation causes a rare form of tubulointerstitial fibrosis ( 37 ), SLC34A2 (sodium-dependent phosphate transport protein 2B; logFC –4.01), which may contribute to the diminution in the uptake of both sodium and phosphate in the proximal tubules in Dent disease patients, the Rab GTPase RAB27B (logFC –1.50), which is involved in exosome secretion, COL4A4 (Collagen Type IV Alpha 4 Chain; logFC –0.92), which is mutated in patients with Alport syndrome, the kidney-specific Cadherin CDH16 (logFC –2.25), which is involved in cell–cell adhesions or KLF4 (Kruppel-like factor 4; logFC –0.99), which has been identified as a renal linage master regulatory transcription factor ( 38 ). Taken together, these results suggest that lack of ClC-5 widely affects the phenotype of RPTEC/TERT1 cells, but it remains to be known whether lack of ClC-5 impacts on these processes through its effect on endosomal acidification, altered chloride transport, protein endocytosis, or its participation in macromolecular complexes.…”

Section: Discussionmentioning

confidence: 99%

Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function

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Burballa

Cantero-Recasens

et al. 2021

Human Molecular Genetics

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Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressing to chronic kidney disease. Although mutations in the electrogenic Cl−/H+ antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype–phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. To further discover the mechanisms linking ClC-5 loss-of-function to proximal tubule dysfunction, we have generated novel DD1 cellular models depleted of ClC-5 and carrying ClC-5 mutants p.(Val523del), p.(Glu527Asp) and p.(Ile524Lys) using the human proximal tubule-derived RPTEC/TERT1 cell line. Our DD1 cellular models exhibit impaired albumin endocytosis, increased substrate adhesion and decreased collective migration, correlating with a less differentiated epithelial phenotype. Despite sharing functional features, these DD1 cell models exhibit different gene expression profiles, being p.(Val523del) ClC-5 the mutation showing the largest differences. Gene set enrichment analysis pointed to kidney development, anion homeostasis, organic acid transport, extracellular matrix organization and cell migration biological processes as the most likely involved in DD1 pathophysiology. In conclusion, our results revealed the pathways linking ClC-5 mutations with tubular dysfunction and, importantly, provide new cellular models to further study DD1 pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function

Durán

Burballa

Cantero-Recasens

et al. 2021

Human Molecular Genetics

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“…[4][5][6][7] Missense mutations in the UMOD gene cause autosomal dominant tubulointerstitial disease (ADTKD-UMOD), an inherited disease characterized by progressive kidney disease with interstitial fibrosis, tubular atrophy and lack of significant glomerular pathology. 8 Many single nucleotide polymorphisms around the UMOD gene are also associated with kidney disease 9 .…”

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confidence: 99%

Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms

et al. 2022

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Uromodulin (or Tamm-Horsfall protein) is a glycoprotein uniquely produced in the kidney by tubular cells of the thick ascending limb of the loop of Henle and early distal tubules. This protein exhibits bidirectional secretion in the urine and in the renal interstitium and circulation. The role of this protein in maintaining renal and systemic homeostasis is becoming increasingly appreciated. Furthermore, perturbations of its functions may play a role in various diseases affecting the kidney and distant organs. In this review, we will discuss important advances in understanding its biology, highlighting the recent discoveries of its secretion and differential precursor processing that generates 2 forms: (1) a highly polymerizing form that is apically excreted in the urine and generates filaments and (2) a nonpolymerizing form that retains a polymerization inhibitory pro-peptide and is released basolaterally in the kidney interstitium and circulation, but can also be found in the urine. We will also discuss factors regulating its production and release, taking into account its intricate physiology, and propose best practices to report its levels. We also discuss breaking advances in its role in hypertension, acute kidney injury and progression to chronic disease, immunomodulation and regulating renal and systemic oxidative stress. We anticipate that this work will be a great resource for researchers and clinicians. This review will highlight the importance of defining what regulates the 2 forms of uromodulin, so that modulation of uromodulin levels and function could become a novel tool in our therapeutic armamentarium against kidney disease.

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Autosomal dominant tubulointerstitial kidney disease: a new tool to guide genetic testing

Cited by 2 publications

References 9 publications

Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function

Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function

Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms

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