67 research outputs found
Parvalbumin: calcium and magnesium buffering in the distal nephron
Parvalbumin (PV) is a classical member of the EF-hand protein superfamily that has been described as a Ca2+ buffer and Ca2+ transporter/shuttle protein and may also play an additional role in Mg2+ handling. PV is exclusively expressed in the early part of the distal convoluted tubule in the human and mouse kidneys. Recent studies in Pvalb knockout mice revealed a role of PV in the distal handling of electrolytes: the lack of PV was associated with a mild salt-losing phenotype with secondary aldosteronism, salt craving and stronger bones compared with controls. A link between the Ca2+-buffering capacity of PV and the expression of the thiazide-sensitive Na+-Clâ cotransporter was established, which could be relevant to the regulation of sodium transport in the distal nephron. Variants in the PVALB gene that encodes PV have been described, but their relevance to kidney function has not been established. PV is also considered a reliable marker of chromophobe carcinoma and oncocytoma, two neoplasms deriving from the distal nephron. The putative role of PV in tumour genesis remains to be investigate
Paradoxical response to furosemide in uromodulin-associated kidney disease
The mechanism by which uromodulin mutations lead to urine concentrating defect in humans remains to be better elucidated .Labriola et al show original data exploring the tubular function of a patient suffering UAKD during the early phase of the diseas
Hepsin-mediated Processing of Uromodulin is Crucial for Salt-sensitivity and Thick Ascending Limb Homeostasis.
Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders. The luminal release and subsequent polymerization of uromodulin depend on its cleavage mediated by the serine protease hepsin. The biological relevance of a proper cleavage of uromodulin remains unknown. Here we combined in vivo testing on hepsin-deficient mice, ex vivo analyses on isolated tubules and in vitro studies on TAL cells to demonstrate that hepsin influence on uromodulin processing is an important modulator of salt transport via the sodium cotransporter NKCC2 in the TAL. At baseline, hepsin-deficient mice accumulate uromodulin, along with hyperactivated NKCC2, resulting in a positive sodium balance and a better adaptation to water deprivation. In conditions of high salt intake, defective uromodulin processing predisposes hepsin-deficient mice to a salt-wasting phenotype, with a decreased salt sensitivity. These modifications are associated with intracellular accumulation of uromodulin, endoplasmic reticulum-stress and signs of tubular damage. These studies expand the physiological role of hepsin and uromodulin and highlight the importance of hepsin-mediated processing of uromodulin for kidney tubule homeostasis and salt sensitivity
An intermediate-effect size variant in UMOD confers risk for chronic kidney disease
The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10(â5) to 10(â3). Among them, the missense variant p.Thr62Pro is detected in âŒ1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD
Filovirus RefSeq Entries: Evaluation and Selection of Filovirus Type Variants, Type Sequences, and Names
Sequence determination of complete or coding-complete genomes of viruses is becoming common practice for supporting the work of epidemiologists, ecologists, virologists, and taxonomists. Sequencing duration and costs are rapidly decreasing, sequencing hardware is under modification for use by non-experts, and software is constantly being improved to simplify sequence data management and analysis. Thus, analysis of virus disease outbreaks on the molecular level is now feasible, including characterization of the evolution of individual virus populations in single patients over time. The increasing accumulation of sequencing data creates a management problem for the curators of commonly used sequence databases and an entry retrieval problem for end users. Therefore, utilizing the data to their fullest potential will require setting nomenclature and annotation standards for virus isolates and associated genomic sequences. The National Center for Biotechnology Informationâs (NCBIâs) RefSeq is a non-redundant, curated database for reference (or type) nucleotide sequence records that supplies source data to numerous other databases. Building on recently proposed templates for filovirus variant naming [ ()////-], we report consensus decisions from a majority of past and currently active filovirus experts on the eight filovirus type variants and isolates to be represented in RefSeq, their final designations, and their associated sequences
Virus nomenclature below the species level : a standardized nomenclature for laboratory animal-adapted strains and variants of viruses assigned to the family Filoviridae
The International Committee on Taxonomy of Viruses (ICTV) organizes the classification of
viruses into taxa, but is not responsible for the nomenclature for taxa members. International
experts groups, such as the ICTV Study Groups, recommend the classification and naming of
viruses and their strains, variants, and isolates. The ICTV Filoviridae Study Group has recently
introduced an updated classification and nomenclature for filoviruses. Subsequently, and
together with numerous other filovirus experts, a consistent nomenclature for their natural
genetic variants and isolates was developed that aims at simplifying the retrieval of sequence
data from electronic databases. This is a first important step toward a viral genome annotation
standard as sought by the US National Center for Biotechnology Information (NCBI). Here, this
work is extended to include filoviruses obtained in the laboratory by artificial selection through
passage in laboratory hosts. The previously developed template for natural filovirus genetic
variant naming ( //<year of
sampling>/-) is retained, but it is proposed to
adapt the type of information added to each field for laboratory animal-adapted variants. For
instance, the full-length designation of an Ebola virus Mayinga variant adapted at the State
Research Center for Virology and Biotechnology âVectorâ to cause disease in guinea pigs after
seven passages would be akin to âEbola virus VECTOR/C.porcellus-lab/COD/1976/Mayinga-
GPA-P7â. As was proposed for the names of natural filovirus variants, we suggest using the fulllength
designation in databases, as well as in the method section of publications. Shortened
designations (such as âEBOV VECTOR/C.por/COD/76/May-GPA-P7â) and abbreviations (such
as âEBOV/May-GPA-P7â) could be used in the remainder of the text depending on how critical it is to convey information contained in the full-length name. âEBOVâ would suffice if only one
EBOV strain/variant/isolate is addressed.This work was funded in part by the Joint Science and Technology Office for Chem Bio Defense (proposal #TMTI0048_09_RD_T to SB).http://www.springerlink.com/content/0304-8608/hb2013ab201
Virus nomenclature below the species level : a standardized nomenclature for filovirus strains and variants rescued from cDNA
Specific alterations (mutations, deletions,
insertions) of virus genomes are crucial for the functional
characterization of their regulatory elements and their expression products, as well as a prerequisite for the creation
of attenuated viruses that could serve as vaccine
candidates. Virus genome tailoring can be performed either
by using traditionally cloned genomes as starting materials,
followed by site-directed mutagenesis, or by de novo synthesis
of modified virus genomes or parts thereof. A systematic
nomenclature for such recombinant viruses is
necessary to set them apart from wild-type and laboratoryadapted
viruses, and to improve communication and collaborations
among researchers who may want to use
recombinant viruses or create novel viruses based on them.
A large group of filovirus experts has recently proposed
nomenclatures for natural and laboratory animal-adapted
filoviruses that aim to simplify the retrieval of sequence
data from electronic databases. Here, this work is extended
to include nomenclature for filoviruses obtained in the
laboratory via reverse genetics systems. The previously
developed template for natural filovirus genetic variant
naming,\virus name[(\strain[/)\isolation host-suffix[/
\country of sampling[/\year of sampling[/\genetic
variant designation[-\isolate designation[, is retained, but we propose to adapt the type of information added to each
field for cDNA clone-derived filoviruses. For instance, the
full-length designation of an Ebola virus Kikwit variant
rescued from a plasmid developed at the US Centers for
Disease Control and Prevention could be akin to ââEbola
virus H.sapiens-rec/COD/1995/Kikwit-abc1ââ (with the
suffix âârecââ identifying the recombinant nature of the virus
and ââabc1ââ being a placeholder for any meaningful isolate
designator). Such a full-length designation should be used
in databases and the methods section of publications.
Shortened designations (such as ââEBOV H.sap/COD/95/
Kik-abc1ââ) and abbreviations (such as ââEBOV/Kik-abc1ââ)
could be used in the remainder of the text, depending on
how critical it is to convey information contained in the
full-length name. ââEBOVââ would suffice if only one
EBOV strain/variant/isolate is addressed.http://link.springer.com/journal/705hb201
Claudins: a tale of interactions in the thick ascending limb
Abstract The claudins are the main proteins composing the tight junctions. The differential expression of claudin isoforms contributes to the specificity of paracellular transport pathways along the kidney tubule. Recent studies focusing on claudin-10 and claudin-16 support the longitudinal specialization of paracellular transport of cations within the thick ascending limb and demonstrate that complex tubular adaptations operate to buffer the consequences of chronic segmental lesions in the kidney
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