Serum uromodulin is inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1 in the population-based KORA F4 study.

Cornelia Then,Barbara Thorand,Wolfgang Rathmann,Holger L Then,Margit Heier,Annette Peters,Martin Reincke,Christa Meisinger,Wolfgang Koenig,Andreas Lechner,Jürgen E Scherberich,Martin Bidlingmaier,Jochen Seissler,Franziska Theilig

doi:10.1371/journal.pone.0237364

Abstract

ObjectivesUromodulin has been associated with arterial hypertension in genome-wide association studies, but data from clinical and preclinical studies are inconsistent. We here analyzed the association of serum uromodulin (sUmod) with arterial hypertension and vasoactive hormones in a population-based study.MethodsIn 1108 participants of the KORA F4 study aged 62–81 years, sUmod was measured and the association of sUmod with arterial hypertension was assessed using logistic regression models. The associations of sUmod with renin and aldosterone and with the vasoconstrictive prohormone C-terminal pro-endothelin-1 (CT-proET-1) were analyzed in 1079 participants and in 618 participants, respectively, using linear regression models.ResultsAfter multivariable adjustment including sex, age, eGFR, BMI, fasting glucose, current smoking, previous stroke and myocardial infarction, sUmod was inversely associated with arterial hypertension (OR 0.78; 95% CI 0.68–0.91; p = 0.001). SUmod was not significantly associated with renin and aldosterone after adjustment for sex, age and eGFR. However, sUmod was inversely associated with CT-proET-1 (β -0.19 ± 0.04; p < 0.001) after adjustment for sex, age, eGFR, BMI, arterial hypertension, fasting glucose, current smoking, previous stroke and myocardial infarction. The association with CT-proET-1 was stronger in participants with hypertension (β -0.22 ± 0.04) than in normotensive participants (β -0.13 ± 0.06; p for interaction hypertension = 0.003 in the model adjusted for hypertension).ConclusionsSUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of sUmod on blood pressure regulation.

Highlights

Uromodulin is a glycosylphosphatidylinositol-anchored protein synthesized in tubular cells of the ascending limb of Henles loop
SUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of serum uromodulin (sUmod) on blood pressure regulation
We further investigated the association of sUmod with renin and aldosterone as well as with the prohormone C-terminal pro-endothelin-1 (CT-proET-1), hypothesizing that these hormones are involved in an endocrine feedback regulation of blood pressure

Summary

Introduction

Uromodulin is a glycosylphosphatidylinositol-anchored protein synthesized in tubular cells of the ascending limb of Henles loop. SUmod seems to play an important role beyond renal homeostasis, since it is inversely associated with all-cause and cardiovascular mortality [14,15,16,17] and with various cardiovascular risk factors, such as diabetes [18, 19], the metabolic syndrome and its single components including elevated blood pressure [20]. Genome-wide association studies [21,22,23,24] and animal models [25, 26] show an increased risk of arterial hypertension in uromodulin-increasing UMOD loci variants, and uromodulin has even been suggested to be a possible target for blood pressure control [26]. Preclinical evidence suggests an interaction of uromodulin with the vasoregulatory renin-angiotensin-aldosterone system [27]

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