Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression
TL;DR: The findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function and the relevance of this mechanism in humans is demonstrated by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressured patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients.
Abstract: Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.
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TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
409 citations
TL;DR: Understanding of its pivotal mechanisms may lead to specific therapies to decrease the cardiovascular risk associated with this trait in humans, and identification of biochemical or genetic markers of salt-sensitivity for use in the clinic would improve risk stratification of hypertensive and prehypertensive subjects.
Abstract: Salt-sensitivity of blood pressure is an abnormal phenotype that confers increased cardiovascular morbidity. We discuss its underlying renal mechanisms, including the role of systems that regulate renal salt handling. We review knockout and congenic strains that have unraveled participation of several genes in rodents inbred to produce pure salt-sensitive and salt-resistant substrains. In humans, salt-sensitivity is a continuous variable, hence, defined with arbitrary cutoffs for blood pressure responses to salt-loading or deprivation. Nonetheless, clustering of phenotypic characteristics in salt-sensitive subjects suggests an inherited component for this trait. This is supported by relationships between salt-sensitivity and gene polymorphisms in renal transporters, vasoactive substances and oxidative systems. Identification of biochemical or genetic markers of salt-sensitivity for use in the clinic would improve risk stratification of hypertensive and prehypertensive subjects. Understanding of its pivotal mechanisms may lead to specific therapies to decrease the cardiovascular risk associated with this trait in humans.
314 citations
TL;DR: The simplest definition of salt sensitivity of blood pressure (SSBP) states that it is a physiological trait present in rodents and other mammals, including humans, by which the blood pressure of some members of the population exhibits changes parallel to changes in salt intake as discussed by the authors.
Abstract: The simplest definition of salt sensitivity of blood pressure (SSBP) states that it is a physiological trait present in rodents and other mammals, including humans, by which the blood pressure (BP) of some members of the population exhibits changes parallel to changes in salt intake. In animals, the trait has been inbred such that the salt-sensitive (SS) ones will sustain increases in BP with salt loading and decreases with salt depletion, whereas the salt resistant (SR) ones will not. In humans, the trait is normally distributed; therefore, the distinction between SS and SR members of the population has been made by choosing an arbitrary magnitude of the salt-induced change in BP to define the groups. Regardless of possible causation by abnormalities of sodium handling, the SS phenotype is not usually characterized by alterations in salt balance (eg, impaired natriuresis or expanded plasma volume) but rather by a hypertensive response to maintain it.
In an unselected population, SSBP is a continuous, normally distributed quantitative trait.1 As with any other trait with these characteristics, there is the issue of whether population members with the largest and smallest quantities of the trait represent the randomness of its distribution or are qualitatively different from the population at large. An example of this controversy is the old analyses of the unimodality versus bimodality of BP incidence or prevalence in humans that tried to determine whether hypertension is a distinct entity or simply an extreme of the gaussian distribution of BP.2 The development of the spontaneously hypertensive rat by Japanese investigators3 showing that the trait could be selected by inbreeding made it clear that hypertension had a genetic component. The gaussian distribution of population BP is probably the result of a random mixture of prohypertensive and antihypertensive genes and genetic variants in a …
251 citations
University of Erlangen-Nuremberg1, Beth Israel Deaconess Medical Center2, Paris Descartes University3, French Institute of Health and Medical Research4, Wake Forest University5, University of Cyprus6, Charles University in Prague7, University of Texas Southwestern Medical Center8, University of Zurich9
TL;DR: Adopting a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria is anticipated to facilitate recognition and characterization of these monogenic diseases.
249 citations
TL;DR: This review summarized the different appearance, cellular origin and major emerging processes and mediators of fibrosis in each compartment of kidney's histological structure, and depicted and discussed the challenges in translation of anti-fibrotic treatment to clinical practice.
247 citations
References
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TL;DR: This study enters into the particular topics of the relative quantification in real-time RT-PCR of a target gene transcript in comparison to a reference gene transcript and presents a new mathematical model that needs no calibration curve.
Abstract: Use of the real-time polymerase chain reaction (PCR) to amplify cDNA products reverse transcribed from mRNA is on the way to becoming a routine tool in molecular biology to study low abundance gene expression. Real-time PCR is easy to perform, provides the necessary accuracy and produces reliable as well as rapid quantification results. But accurate quantification of nucleic acids requires a reproducible methodology and an adequate mathematical model for data analysis. This study enters into the particular topics of the relative quantification in real-time RT–PCR of a target gene transcript in comparison to a reference gene transcript. Therefore, a new mathematical model is presented. The relative expression ratio is calculated only from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. This model needs no calibration curve. Control levels were included in the model to standardise each reaction run with respect to RNA integrity, sample loading and inter-PCR variations. High accuracy and reproducibility (<2.5% variation) were reached in LightCycler PCR using the established mathematical model.
30,462 citations
TL;DR: This chapter assumes acquaintance with the principles and practice of PCR, as outlined in, for example, refs.
Abstract: 1. Introduction Designing PCR and sequencing primers are essential activities for molecular biologists around the world. This chapter assumes acquaintance with the principles and practice of PCR, as outlined in, for example, refs. 1–4. Primer3 is a computer program that suggests PCR primers for a variety of applications, for example to create STSs (sequence tagged sites) for radiation hybrid mapping (5), or to amplify sequences for single nucleotide polymor-phism discovery (6). Primer3 can also select single primers for sequencing reactions and can design oligonucleotide hybridization probes. In selecting oligos for primers or hybridization probes, Primer3 can consider many factors. These include oligo melting temperature, length, GC content , 3′ stability, estimated secondary structure, the likelihood of annealing to or amplifying undesirable sequences (for example interspersed repeats), the likelihood of primer–dimer formation between two copies of the same primer, and the accuracy of the source sequence. In the design of primer pairs Primer3 can consider product size and melting temperature, the likelihood of primer– dimer formation between the two primers in the pair, the difference between primer melting temperatures, and primer location relative to particular regions of interest or to be avoided.
16,407 citations
Journal Article•
TL;DR: In the early 1990s, the National Kidney Foundation (K/DOQI) developed a set of clinical practice guidelines to define chronic kidney disease and to classify stages in the progression of kidney disease.
10,265 citations
TL;DR: Jalview 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server.
Abstract: Summary: Jalview Version 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments. Core features include keyboard and mouse-based editing, multiple views and alignment overviews, and linked structure display with Jmol. Jalview 2 is available in two forms: a lightweight Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server.
Availability: The Jalview 2 Desktop application and JalviewLite applet are made freely available under the GPL, and can be downloaded from www.jalview.org
Contact: g.j.barton@dundee.ac.uk
7,926 citations
TL;DR: The overall prevalence and absolute burden of hypertension in 2000 and the global burden in 2025 were estimated to be about 1.56 billion (1.54-1.58 billion) and the number of adults with hypertension in 2025 was predicted to increase by about 60% respectively.
7,633 citations