Uromodulin, an Emerging Novel Pathway for Blood Pressure Regulation and Hypertension

Padmanabhan, Sandosh; Graham, Lesley; Ferreri, Nicholas R.; Graham, Delyth; McBride, Martin W.; Dominiczak, Anna F.

doi:10.1161/hypertensionaha.114.03132

Cited by 44 publications

(32 citation statements)

References 67 publications

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“…The relationship between FE-Na and uromodulin in individuals in steady state could be explained by a higher sodium intake leading to ECV expansion, a reduced proximal tubule sodium reabsorption, greater sodium delivery to the TAL, and greater TAL activity and uromodulin excretion. Of interest, uromodulin knockout mice failed to increase BP after 2% NaCl infusion, contrary to wild-type mice, indicating a role for uromodulin in regulating sodium uptake in the TAL (39,40). The influence of common variants in KCNJ1, CAB39, and SORL1, which all regulate sodium reabsorption in the TAL, on uromodulin excretion levels in the general population (19) as well as the greater response to furosemide in patients who are hypertensive with UMOD variants (18) also support the latter hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

Troyanov

Delmas-Frenette

Bollée

et al. 2016

Clinical Journal of the American Society of Nephrology

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Background and objectives The urinary excretion of uromodulin is influenced by common variants in the UMOD gene, and it may be related to NaCl retention and hypertension. Levels of uromodulin are also dependent of the renal function, but other determinants remain unknown.Design, setting, participants, & measurements We tested associations between the urinary excretion of uromodulin; medical history and medication; serum and urinary levels of electrolytes, glucose, and uric acid; and the genotype at the UMOD/Protein Disulfide Isomerase-Like, Testis Expressed locus (rs4293393 and rs12446492); 943 participants from the CARTaGENE Cohort, a random sample from the Canadian population of 20,004 individuals, were analyzed. Participants with available genotyping were obtained from a substudy addressing associations between common variants and cardiovascular disease in paired participants with high and low Framingham risk scores and vascular rigidity indexes.Results The population studied was 5469 years old, with 51% women and eGFR of 9614 ml/min per 1.73 m 2 . Uromodulin excretion was 25 (11-42) mg/g creatinine. Using linear regression, it was independently higher among patients with higher eGFR, the TT genotype of rs4293393, and the TT genotype of rs12446492. The fractional excretions of urate and sodium showed a strong positive correlation with uromodulin, likely linked to the extracellular volume status. The presence of glycosuria and the use of uricosuric drugs, which both increased the fraction excretion of urate, were independently associated with a lower uromodulin excretion, suggesting novel interactions between uric acid and uromodulin excretion. ConclusionsIn this large cohort, the excretion of uromodulin correlates with clinical, genetic, and urinary factors. The strongest associations were between uric acid, sodium, and uromodulin excretions and are likely linked to the extracellular volume status.

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Section: Discussionmentioning

confidence: 99%

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

Troyanov

Delmas-Frenette

Bollée

et al. 2016

Clinical Journal of the American Society of Nephrology

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“…30,32,77 In a GWAS of BP extremes, the minor G allele of a UMOD promoter SNP, rs13333226, was associated with a lower risk of hypertension (odds ratio [95% confidence interval], 0.87 [0.84-0.91]) and reduced urinary UMOD excretion. 22 Mechanistic studies in mouse models showed that UMOD knockout mice had significantly lower systolic BP than wildtype mice, were resistant to salt-induced changes of BP, and demonstrated a leftward shift of the pressure-natriuresis curve.…”

Section: Common Variants and Novel Pathwaysmentioning

confidence: 99%

Genetic and Molecular Aspects of Hypertension

Padmanabhan

Caulfield

Dominiczak

2015

Circulation Research

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172

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Understanding the complex nature of BP regulation accelerated after William Harvey description of the circulatory system in the 17th century, with each incremental advance reinforcing its multifactorial basis, and highlighted by Guyton iconic computer model of circulatory (BP) control in 1972 which incorporated empirically tested concepts of blood flow autoregulation and the pressure-natriuresis relationship.

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“…118 A newly discovered pathway modulated by the uromodulin gene shows promise in yielding future drug targets. 119 Evidence from genetic studies also suggests that mechanisms involved in the regulation of NPs could be considered as a potential target or marker of response. Hence, activators of NPs, such as corin, NP target receptors, or enzymes involved in the degradation of NP exhibit a level of expression or activity influenced by genetic variation.…”

Section: Future Tools and Targets For Drug Developmentmentioning

confidence: 99%

Interventional procedures and future drug therapy for hypertension

2016

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Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care.

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Uromodulin, an Emerging Novel Pathway for Blood Pressure Regulation and Hypertension

Cited by 44 publications

References 67 publications

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

Genetic and Molecular Aspects of Hypertension

Interventional procedures and future drug therapy for hypertension

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