Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases

Yong, Li; Cheng, Yu-Rong; Consolato, Francesco; Schiano, Guglielmo; Chong, Michael; Pietzner, Maik; Nguyen, Ngoc Quynh; Scherer, Nora; Biggs, Mary L.; Kleber, Marcus E.; Haug, Stefan; Göçmen, Burulça; Pigeyre, Marie; Sekula, Peggy; Steinbrenner, Inga; Schlosser, Pascal; Joseph, Christina B.; Brody, Jennifer A.; Grams, Morgan E.; Hayward, Caroline; Schultheiss, Ulla T.; Krämer, Bernhard K.; Kronenberg, Florian; Peters, Annette; Seißler, Jochen; Steubl, Dominik; Then, Cornelia; Wuttke, Matthias; März, Winfried; Eckardt, Kai Uwe; Gieger, Christian; Boerwinkle, Eric; Psaty, Bruce M.; Coresh, Josef; Oefner, Peter J.; Paré, Guillaume; Langenberg, Claudia; Scherberich, Jürgen E.; Yu, Bing; Akilesh, Shreeram; Devuyst, Olivier; Rampoldi, Luca; Köttgen, Anna

doi:10.1172/jci.insight.157035

Cited by 15 publications

(14 citation statements)

References 79 publications

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“…The mechanisms regulating the basolateral trafficking of uromodulin and its release into the interstitium and further into the circulation remain essentially unknown. A recent meta-GWAS of circulating uromodulin using different detection methods revealed that a missense variant (p.Cys466Arg) in the uromodulin-glycosylating enzyme B4GALNT2 was a loss-of-function allele leading to higher serum uromodulin levels, while other loci influence the glycosylation of circulating uromodulin [ 33 ]. The current view is that interstitial uromodulin may cross talk with proximal tubule cells, contributing to regulate innate immunity, whereas circulating uromodulin may act as an anti-oxidant [ 53 ].…”

Section: Biological Relevance Of the Umod Locus Fo...mentioning

confidence: 99%

UMOD and the architecture of kidney disease

Devuyst

Bochud

Olinger

2022

Pflugers Arch - Eur J Physiol

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The identification of genetic factors associated with the risk, onset, and progression of kidney disease has the potential to provide mechanistic insights and therapeutic perspectives. In less than two decades, technological advances yielded a trove of information on the genetic architecture of chronic kidney disease. The spectrum of genetic influence ranges from (ultra)rare variants with large effect size, involved in Mendelian diseases, to common variants, often non-coding and with small effect size, which contribute to polygenic diseases. Here, we review the paradigm of UMOD, the gene coding for uromodulin, to illustrate how a kidney-specific protein of major physiological importance is involved in a spectrum of kidney disorders. This new field of investigation illustrates the importance of genetic variation in the pathogenesis and prognosis of disease, with therapeutic implications.

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Section: Biological Relevance Of the Umod Locus Fo...mentioning

confidence: 99%

UMOD and the architecture of kidney disease

Devuyst

Bochud

Olinger

2022

Pflugers Arch - Eur J Physiol

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“…Recent work from GWAS studies suggest that single nucleotide polymorphisms linked to circulating uromodulin are different compared with urine uromodulin. 7 A more detailed description of the genetic factors determining uromodulin expression and secretion is found in the Supplemental Material and summarized in Table S4.…”

Section: Polymerizing and Nonpolymerizing (Including Circulating) Uro...mentioning

confidence: 99%

“…The association of uromodulin levels, polymorphisms, and mutations with acute and chronic forms of renal disease argues for important regulatory functions of this glycoprotein in maintaining a healthy renal milieu. [4][5][6][7] Missense mutations in the UMOD gene cause autosomal dominant tubulointerstitial disease (ADTKD-UMOD), an inherited disease characterized by progressive kidney disease with interstitial fibrosis, tubular atrophy and lack of significant glomerular pathology. 8 Many single nucleotide polymorphisms around the UMOD gene are also associated with kidney disease 9 .…”

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confidence: 99%

Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms

et al. 2022

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Uromodulin (or Tamm-Horsfall protein) is a glycoprotein uniquely produced in the kidney by tubular cells of the thick ascending limb of the loop of Henle and early distal tubules. This protein exhibits bidirectional secretion in the urine and in the renal interstitium and circulation. The role of this protein in maintaining renal and systemic homeostasis is becoming increasingly appreciated. Furthermore, perturbations of its functions may play a role in various diseases affecting the kidney and distant organs. In this review, we will discuss important advances in understanding its biology, highlighting the recent discoveries of its secretion and differential precursor processing that generates 2 forms: (1) a highly polymerizing form that is apically excreted in the urine and generates filaments and (2) a nonpolymerizing form that retains a polymerization inhibitory pro-peptide and is released basolaterally in the kidney interstitium and circulation, but can also be found in the urine. We will also discuss factors regulating its production and release, taking into account its intricate physiology, and propose best practices to report its levels. We also discuss breaking advances in its role in hypertension, acute kidney injury and progression to chronic disease, immunomodulation and regulating renal and systemic oxidative stress. We anticipate that this work will be a great resource for researchers and clinicians. This review will highlight the importance of defining what regulates the 2 forms of uromodulin, so that modulation of uromodulin levels and function could become a novel tool in our therapeutic armamentarium against kidney disease.

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“…However, a monomeric form is also secreted into the blood (circulating or serum uromodulin) via the basolateral membrane and is detected at levels 100- to 1000-fold lower than in urine. 27 N-glycans are likely to play a key role in the polarized sorting of uromodulin 28,29 ; however, further research into the precise mechanisms is warranted. Similarly, the trafficking proteins involved in the transport of uromodulin are also not well understood.…”

Section: Gene To Proteinmentioning

confidence: 99%

Role of Uromodulin in Salt-Sensitive Hypertension

et al. 2022

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The exclusive expression of uromodulin in the kidneys has made it an intriguing protein in kidney and cardiovascular research. Genome-wide association studies discovered variants of uromodulin that are associated with chronic kidney diseases and hypertension. Urinary and circulating uromodulin levels reflect kidney and cardiovascular health as well as overall mortality. More recently, Mendelian randomization studies have shown that genetically driven levels of uromodulin have a causal and adverse effect on kidney function. On a mechanistic level, salt sensitivity is an important factor in the pathophysiology of hypertension, and uromodulin is involved in salt reabsorption via the NKCC2 (Na + -K + -2Cl − cotransporter) on epithelial cells of the ascending limb of loop of Henle. In this review, we provide an overview of the multifaceted physiology and pathophysiology of uromodulin including recent advances in its genetics; cellular trafficking; and mechanistic and clinical studies undertaken to understand the complex relationship between uromodulin, blood pressure, and kidney function. We focus on tubular sodium reabsorption as one of the best understood and pathophysiologically and clinically most important roles of uromodulin, which can lead to therapeutic interventions.

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Genome-wide studies reveal factors associated with circulating uromodulin and its relationships to complex diseases

Cited by 15 publications

References 79 publications

UMOD and the architecture of kidney disease

UMOD and the architecture of kidney disease

Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms

Role of Uromodulin in Salt-Sensitive Hypertension

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