The Role of Uromodulin in Cardiovascular Disease: a Review

Overview

Journal Front Cardiovasc Med

Specialty Cardiology & Vascular Diseases

Date 2024 Jul 25

PMID 39049957

Authors

Chengqian Chen

Wentao Zhong

Hao Zheng

Gaoying Dai

Wei Zhao

Yushi Wang

Qi Dong

Botao Shen

Affiliations

Soon will be listed here.

Abstract

Uromodulin, also referred to as Tamm Horsfall protein (THP), is a renal protein exclusively synthesized by the kidneys and represents the predominant urinary protein under normal physiological conditions. It assumes a pivotal role within the renal system, contributing not only to ion transport and immune modulation but also serving as a critical factor in the prevention of urinary tract infections and kidney stone formation. Emerging evidence indicates that uromodulin may serve as a potential biomarker extending beyond renal function. Recent clinical investigations and Mendelian randomization studies have unveiled a discernible association between urinary regulatory protein levels and cardiovascular events and mortality. This review primarily delineates the intricate relationship between uromodulin and cardiovascular disease, elucidates its predictive utility as a novel biomarker for cardiovascular events, and delves into its involvement in various physiological and pathophysiological facets of the cardiovascular system, incorporating recent advancements in corresponding genetics.

References

Onnis C, Virmani R, Kawai K, Nardi V, Lerman A, Cademartiri F . Coronary Artery Calcification: Current Concepts and Clinical Implications. Circulation. 2024; 149(3):251-266. PMC: 10794033. DOI: 10.1161/CIRCULATIONAHA.123.065657. View

Mo L, Zhu X, Huang H, Shapiro E, Hasty D, Wu X . Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli. Am J Physiol Renal Physiol. 2003; 286(4):F795-802. DOI: 10.1152/ajprenal.00357.2003. View

Bjugn R, Flood P . Scanning electron microscopy of human urine and purified Tamm-Horsfall's glycoprotein. Scand J Urol Nephrol. 1988; 22(4):313-5. DOI: 10.3109/00365598809180806. View

Tadic M, Cuspidi C, Marwick T . Phenotyping the hypertensive heart. Eur Heart J. 2022; 43(38):3794-3810. DOI: 10.1093/eurheartj/ehac393. View

Caceres P, Ortiz P . Molecular regulation of NKCC2 in blood pressure control and hypertension. Curr Opin Nephrol Hypertens. 2019; 28(5):474-480. PMC: 7226929. DOI: 10.1097/MNH.0000000000000531. View

Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V . Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice. Am J Physiol Renal Physiol. 2004; 288(3):F559-67. DOI: 10.1152/ajprenal.00143.2004. View

Graham L, Padmanabhan S, Fraser N, Kumar S, Bates J, Raffi H . Validation of uromodulin as a candidate gene for human essential hypertension. Hypertension. 2013; 63(3):551-8. DOI: 10.1161/HYPERTENSIONAHA.113.01423. View

Zimmerhackl L, Rostasy K, Wiegele G, Rasenack A, Wilhelm C, LOHNER M . Tamm-Horsfall protein as a marker of tubular maturation. Pediatr Nephrol. 1996; 10(4):448-52. DOI: 10.1007/s004670050137. View

Nie M, Bal M, Yang Z, Liu J, Rivera C, Wenzel A . Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients. J Am Soc Nephrol. 2016; 27(11):3447-3458. PMC: 5084893. DOI: 10.1681/ASN.2015101100. View

10.

Sharma P, Roy A, Dhamija R, Bhushan S, Baswal K, Kulandaisamy R . A comprehensive proteomic profiling of urinary exosomes and the identification of early non-invasive biomarker in patients with coronary artery disease. J Proteomics. 2023; 293:105059. DOI: 10.1016/j.jprot.2023.105059. View

11.

Leiherer A, Muendlein A, Saely C, Brandtner E, Geiger K, Fraunberger P . The value of uromodulin as a new serum marker to predict decline in renal function. J Hypertens. 2017; 36(1):110-118. DOI: 10.1097/HJH.0000000000001527. View

12.

Takata T, Isomoto H . The Versatile Role of Uromodulin in Renal Homeostasis and Its Relevance in Chronic Kidney Disease. Intern Med. 2023; 63(1):17-23. PMC: 10824655. DOI: 10.2169/internalmedicine.1342-22. View

13.

Thomas D, Davies M, Williams J . Release of gelatinase and superoxide from human mononuclear phagocytes in response to particulate Tamm Horsfall protein. Am J Pathol. 1993; 142(1):249-60. PMC: 1886823. View

14.

Stsiapanava A, Xu C, Brunati M, Zamora-Caballero S, Schaeffer C, Bokhove M . Cryo-EM structure of native human uromodulin, a zona pellucida module polymer. EMBO J. 2020; 39(24):e106807. PMC: 7737619. DOI: 10.15252/embj.2020106807. View

15.

Da Costa C, Leszek Paccolat C, Ponte B . [Sodium, potassium and arterial hypertension: what's new?]. Rev Med Suisse. 2022; 18(795):1694-1697. DOI: 10.53738/REVMED.2022.18.795.1694. View

16.

Sandoval P, Claxton J, Lee J, Saeed F, Hoffert J, Knepper M . Systems-level analysis reveals selective regulation of Aqp2 gene expression by vasopressin. Sci Rep. 2016; 6:34863. PMC: 5057153. DOI: 10.1038/srep34863. View

17.

Medina-Leyte D, Zepeda-Garcia O, Dominguez-Perez M, Gonzalez-Garrido A, Villarreal-Molina T, Jacobo-Albavera L . Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches. Int J Mol Sci. 2021; 22(8). PMC: 8068178. DOI: 10.3390/ijms22083850. View

18.

Karagiannidis A, Theodorakopoulou M, Pella E, Sarafidis P, Ortiz A . Uromodulin biology. Nephrol Dial Transplant. 2024; 39(7):1073-1087. PMC: 11210992. DOI: 10.1093/ndt/gfae008. View

19.

Fang L, Li D, Welling P . Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel function by different mechanisms. Am J Physiol Renal Physiol. 2010; 299(6):F1359-64. PMC: 3006317. DOI: 10.1152/ajprenal.00257.2010. View

20.

Muchmore A . Uromodulin: an immunoregulatory glycoprotein isolated from pregnancy urine that binds to and regulates the activity of interleukin 1. Am J Reprod Immunol Microbiol. 1986; 11(3):89-93. DOI: 10.1111/j.1600-0897.1986.tb00037.x. View