Activation of the Bumetanide-sensitive Na+,K+,2Cl− Cotransporter (NKCC2) Is Facilitated by Tamm-Horsfall Protein in a Chloride-sensitive Manner

Mutig, Kerim; Kahl, Thomas; Saritas, Turgay; Godes, Michael; Persson, Pontus B.; Bates, James M.; Raffi, Hajamohideen S.; Rampoldi, Luca; Uchida, Shinichi; Hille, Carsten; Dosche, Carsten; Kumar, Satish; Castañeda‐Bueno, María; Gamba, Gerardo; Bachmann, S.

doi:10.1074/jbc.m111.222968

Cited by 147 publications

(140 citation statements)

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“…It has been hypothesized that defective reabsorption of NaCl in the TAL may lead to volume contraction and a secondary increase in proximal tubule reabsorption of Ua (31). Of note, uromodulin knockout mice display a reduced NKCC2 cotransporter phosphorylation, whereas overexpression of uromodulin in vitro increases NKCC2 phosphorylation (11). Furthermore, uromodulin increases the activity of ROMK, which supports the view that it modulates NKCC2-dependent NaCl reabsorption in the TAL (12,32,33).…”

Section: Discussionmentioning

confidence: 70%

“…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: 90%

“…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: Introductionmentioning

confidence: 98%

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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: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 90%

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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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“…In line with this finding, studies based on in vitro and in vivo mouse models have documented that uromodulin regulates transport processes operating in the TAL (i.e., the functionally coupled sodium cotransporter NKCC2 and potassium channel ROMK) (4,29). A recent meta-analysis of the genetic determinants of urinary uromodulin revealed that variants in KCNJ1 (ROMK), CAB39, and SORL1 genes, which are all involved in regulating sodium transport in the TAL, were 2 .…”

Section: Discussionmentioning

confidence: 81%

Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population

Pruijm¹,

Ponte²,

Ackermann³

et al. 2016

Clinical Journal of the American Society of Nephrology

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Background and objectives Allelic variants in UMOD, the gene coding for uromodulin, are associated with rare tubulointerstitial kidney disorders and risk of CKD and hypertension in the general population. The factors associated with uromodulin excretion in the normal population remain largely unknown, and were therefore explored in this study.Design, setting, participants, & measurements Urinary uromodulin excretion was measured using a validated ELISA in two population-based cohorts that included more than 6500 individuals. The Swiss Kidney Project on Genes in Hypertension study (SKIPOGH) included 817 adults (mean age6SD, 45617 years) who underwent renal ultrasonography and performed a 24-hour urine collection. The Cohorte Lausannoise study included 5706 adults (mean age, 53611 years) with fresh spot morning urine samples. We calculated eGFRs using the CKDEpidemiology Collaboration formula and by 24-hour creatinine clearance.Results In both studies, positive associations were found between uromodulin and urinary sodium, chloride, and potassium excretion and osmolality. In SKIPOGH, 24-hour uromodulin excretion (median, 41 [interquartile range, 29-57] mg/24 h) was positively associated with kidney length and volume and with creatinine excretion and urine volume. It was negatively associated with age and diabetes. Both spot uromodulin concentration and 24-hour uromodulin excretion were linearly and positively associated (multivariate analyses) with eGFR,90 ml/min per 1.73 m 2 .Conclusion Age, creatinine excretion, diabetes, and urinary volume are independent clinical correlates of urinary uromodulin excretion. The associations of uromodulin excretion with markers of tubular functions and kidney dimensions suggest that it may reflect tubule activity in the general population.

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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%