The UMOD Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease

Devuyst, Olivier; Pattaro, Cristian

doi:10.1681/asn.2017070716

Cited by 63 publications

(65 citation statements)

References 95 publications

(104 reference statements)

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“…Tamm–Horsfall glycoprotein is the most abundant “normal” physiological protein found in urine, with tendency to aggregate and form filamentous meshworks to actively bind urinary particles, apoptotic cells and interact directly with uropathogenic bacteria . Accordingly, THP appears to protect against urinary tract infections but also prevents, e.g., calcium crystal formation and kidney stones .…”

Section: Discussionmentioning

confidence: 99%

Management of Tamm–Horsfall Protein for Reliable Urinary Analytics

Barreiro

Musante

et al. 2019

Proteomics Clinical Apps

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PurposeUrinary extracellular vesicles (uEVs) are a novel source of biomarkers. However, urinary Tamm–Horsfall Protein (THP; uromodulin) interferes with all vesicle isolation attempts, precipitates with normal urinary proteins, thus, representing an unwanted “contaminant” in urinary assays. Thus, the aim is to develop a simple method to manage THP efficiently.Experimental designThe uEVs are isolated by hydrostatic filtration dialysis (HFD) and treated with a defined solution of urea to optimize release of uEVs from sample. Presence of uEVs is confirmed by transmission electron microscopy, Western blotting, and proteomic profiling in MS.ResultsUsing HFD with urea treatment for uEV isolation reduces sample complexity to a great extent. The novel simplified uEV isolation protocol allows comprehensive vesicle proteomics analysis and should be part of any urine analytics to release all sample constituents from THP trap.Conclusions and clinical relevanceThe method brings a quick and easy protocol for THP management during uEV isolation, providing major benefits for comprehensive sample analytics.

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Section: Discussionmentioning

confidence: 99%

Management of Tamm–Horsfall Protein for Reliable Urinary Analytics

Barreiro

Musante

et al. 2019

Proteomics Clinical Apps

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“…One of the areas of debate recently has been the opposing effect on kidney function between the level of expression of THP and the presence of particular SNPs in the UMOD gene promoter area uncovered from genome wide association studies (GWAS) studies [97,98]. We believe that the confusion developed because of data interpretation.…”

Section: O P P O S I N G E F F E C T S B E T W E E N U M O D P R O Mmentioning

confidence: 99%

Uromodulin (Tamm–Horsfall protein): guardian of urinary and systemic homeostasis

Micanovic

LaFavers

Garimella

et al. 2019

Nephrology Dialysis Transplantation

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Biology has taught us that a protein as abundantly made and conserved among species as Tamm-Horsfall protein (THP or uromodulin) cannot just be a waste product serving no particular purpose. However, for many researchers, THP is merely a nuisance during urine proteome profiling or exosome purification and for clinicians an enigmatic entity without clear disease implications. Thanks to recent human genetic and correlative studies and animal modeling, we now have a renewed appreciation of this highly prevalent protein in not only guarding urinary homeostasis, but also serving as a critical mediator in systemic interorgan signaling. Beyond a mere barrier that lines the tubules, or a surrogate for nephron mass, mounting evidence suggests that THP is a multifunctional protein critical for modulating renal ion channel activity, salt/water balance, renal and systemic inflammatory response, intertubular communication, mineral crystallization and bacterial adhesion. Indeed, mutations in THP cause a group of inherited kidney diseases, and altered THP expression is associated with increased risks of urinary tract infection, kidney stone, hypertension, hyperuricemia and acute and chronic kidney diseases. Despite the recent surge of information surrounding THP's physiological functions and disease involvement, our knowledge remains incomplete regarding how THP is normally regulated by external and intrinsic factors, how precisely THP deficiency leads to urinary and systemic pathophysiology and in what clinical settings THP can be used as a theranostic biomarker and a target for modulation to improve patient outcomes.

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“…Genome-wide association studies (GWAS) have identified more than 100 risk loci in the human genome associated with a higher risk for developing chronic kidney disease [56,76,55,68]. Consistently, associations were found for markers next to the gene locus harboring SLC34A1 with significant odds ratios for developing CKD between 1.05 and 1.10 in a cohort of European and mixed Asian, African and European descent, respectively [18]. However, none of these markers resides within the coding region of SLC34A1 and no studies have been undertaken to test the impact of these SNPs on SLC34A1 expression.…”

Section: Napi-iia and Chronic Kidney Diseasementioning

confidence: 80%

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

Lederer

Wagner

2018

Pflugers Arch - Eur J Physiol

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The Na-dependent phosphate transporter NaPi-IIa (SLC34A1) is mostly expressed in kidney, whereas NaPi-IIb (SLC34A2) has a wider tissue distribution with prominent expression in the lung and small intestine. NaPi-IIa is involved in renal reabsorption of inorganic phosphate (Pi) from urine, and patients with biallelic inactivating mutations in SLC34A1 develop hypophosphatemia, hypercalcemia, hypercalciuria and nephrocalcinosis, and nephrolithiasis in early childhood. Monoallelic mutations are frequent in the general population and may impact on the risk to develop kidney stones in adulthood. SNPs in close vicinity to the SLC34A1 locus associate with the risk to develop CKD. NaPi-IIb mediates high-affinity transport of Pi from the diet and appears to be mostly important during low Pi availability. Biallelic inactivating SLC34A2 mutations are found in patients with pulmonary alveolar microlithiasis, a lung disease characterized by the deposition of microcrystals. In contrast, no evidence for disturbed systemic Pi homeostasis has been reported in these patients to date. Nevertheless, NaPi-IIb-mediated intestinal Pi absorption may be a target for pharmaceutical interventions in patients with chronic kidney disease and Pi overload.

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The UMOD Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease

Cited by 63 publications

References 95 publications

Management of Tamm–Horsfall Protein for Reliable Urinary Analytics

Management of Tamm–Horsfall Protein for Reliable Urinary Analytics

Uromodulin (Tamm–Horsfall protein): guardian of urinary and systemic homeostasis

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

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