Tamm-Horsfall Glycoprotein Interacts with Renal Outer Medullary Potassium Channel ROMK2 and Regulates Its Function

Renigunta, Aparna; Renigunta, Vijay; Saritas, Turgay; Decher, Niels; Mutig, Kerim; Waldegger, Siegfried

doi:10.1074/jbc.m110.149880

Cited by 106 publications

(104 citation statements)

References 41 publications

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“…The mechanisms by which defective trafficking of mutant uromodulin leads to hyperuricemia are uncertain, but defective urine concentrating ability suggests a mechanism linked to volume contraction (5). This hypothesis is supported by a reduced TAL sodium reabsorption in uromodulindeficient mice (11,12).…”

Section: Introductionsupporting

confidence: 56%

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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: Introductionsupporting

confidence: 56%

“…Recent findings have shed light on the physiologic role of uromodulin (20), including studies in knockout mice evidencing a link between uromodulin and regulation of sodium transport in the TAL (11,12) as well as previous data showing that uromodulin expression increases with salt intake in animal models (21).…”

Section: Introductionmentioning

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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“…24 Recently, it was found that UMOD had an effect on the renal outer medullary potassium channels (ROMK2), and thus increased salt reabsorption along the TAL. 7 According to these findings, it appeared that UMOD excretion may induce changes in sodium reabsorption in the TAL, thus influencing sodium reabsorption in the proximal tubules as well. Because UMOD may be involved in the regulation of sodium reabsorption, it is reasonable to hypothesize that UMOD influences BP.…”

Section: Discussionmentioning

confidence: 94%

“…Recently, it is found that UMOD has an effect on renal outer medullary potassium channels and thus regulate salt reabsorption along the thick ascending limb. 7 Furthermore, in a genome-wide association study, one of the common variants of UMOD, rs13333226, is identified as being associated with HTN and cardiovascular risk in European cohorts. 8 We therefore systematically genotyped common variants across the UMOD gene in a community-based cohort and explored whether common variants of the UMOD gene are associated with BP.…”

Section: Introductionmentioning

confidence: 99%

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

et al. 2012

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Hypertension is an important risk factor for chronic kidney disease. The kidney, in turn, has an important role in the regulation of blood pressure (BP). On the basis of a genome-wide association study, single-nucleotide polymorphisms in the uromodulin (UMOD) promoter region had been considered to influence both renal sodium reabsorption and BP. In this study, we asked whether common variants across the UMOD gene influence BP in a community-based Chinese cohort. We screened seven common variants across the UMOD locus in a community-based population from Beijing, including 1000 individuals with 48% males and an average age of 63.7 ± 9.0 years. The urinary UMOD concentration was measured by enzyme-linked immunosorbent assay. We then analyzed the association of common variants of UMOD with BP. The UMOD promoter common variant rs13333226 G/A is associated with diastolic BP (DBP), and G allele carriers have higher DBP compared with A/A homozygotes (P ¼ 0.035). The variant rs6497476 C/T predicted the DBP level, with C homozygotes having a higher DBP compared with CT heterozygotes and T homozygotes (P ¼ 0.025). Urinary UMOD excretion was correlated with urinary sodium excretion (R ¼ 0.239, P ¼ 0.656*10 À13 ). We determined that common variants of UMOD are associated with DBP level in a community-based Chinese cohort.

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“…There is evidence that uromodulin in the polymerized form contributes to the water impermeability of TAL [5]. In addition, uromodulin increases membrane expression of the renal outer medullary potassium channel (ROMK2) and activates the TAL N-K-2Cl co-transporter in vitro [12,13]. Disruption of these pathways may contribute to the mild salt and water wasting seen in UMOD mutations, but this remains to be studied.…”

Section: Functions Of Uromodulinmentioning

confidence: 99%