Explore the vast range of titles available.

Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including ‘Medullary Cystic Kidney Disease (MCKD) type 2’, ‘Familial Juvenile Hyperuricemic Nephropathy (FJHN)’, or ‘Uromodulin-Associated Kidney Disease (UAKD)’ for UMOD-related diseases and ‘MCKD type 1’ for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term ‘Autosomal Dominant Tubulointerstitial Kidney Disease’ (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

Uromodulin (Tamm–Horsfall protein) is the most abundant protein excreted in the urine under physiological conditions. It is exclusively produced in the kidney and secreted into the urine via proteolytic cleavage. Its biological function is still not fully understood. Uromodulin has been linked to water/electrolyte balance and to kidney innate immunity. Also, studies in knockout mice demonstrated that it has a protective role against urinary tract infections and renal stone formation. Mutations in the gene encoding uromodulin lead to rare autosomal dominant diseases, collectively referred to as uromodulin-associated kidney diseases. They are characterized by progressive tubulointerstitial damage, impaired urinary concentrating ability, hyperuricemia, renal cysts, and progressive renal failure. Novel in vivo studies point at intracellular accumulation of mutant uromodulin as a key primary event in the disease pathogenesis. Recently, genome-wide association studies identified uromodulin as a risk factor for chronic kidney disease (CKD) and hypertension, and suggested that the level of uromodulin in the urine could represent a useful biomarker for the development of CKD. In this review, we summarize these recent investigations, ranging from invalidation studies in mouse to Mendelian disorders and genome-wide associations, which led to a rediscovery of uromodulin and boosted the scientific and clinical interest for this long discovered molecule.

Background Autosomal dominant tubulointerstitial kidney disease caused by uromodulin mutation (ADTKD-UMOD) is a hereditary condition characterized by progressive renal dysfunction, often requiring renal replacement therapy by middle age. A notable feature is a strong family history of chronic kidney disease (CKD) and hyperuricemia; however, the absence of urinary abnormalities often delays diagnosis. To facilitate early CKD management, a diagnostic method that is simpler than genetic analysis yet strongly indicative of ADTKD-UMOD is needed. Methods Serum and urinary UMOD levels were measured in patients with ADTKD-UMOD, healthy controls, and patients with other diseases. We investigated whether reduced UMOD levels are a distinctive feature of ADTKD-UMOD. Results In 13 cases of ADTKD-UMOD, the serum UMOD (sUMOD) was 24.5 ± 13.9 ng/ml, the serum UMOD/GFR (sUMOD/GFR) was 1.23 ± 0.96, and the urinary UMOD/Cr (uUMOD/Cr) was 1.8 ± 0.9 mg/gcr. In the ADTKD-UMOD dataset, the sUMOD values were significantly lower than those in the other disease datasets. The UMOD/Cr and sUMOD/eGFR values also tended to be lower, although statistically significant differences were observed only in limited comparisons. The ROC analysis revealed that a serum UMOD concentration of < 56.4 ng/ml or sUMOD/GFR of < 1.71 is strongly suggestive of ADTKD-UMOD. Conclusions Measurement of UMOD protein levels is a useful tool for the diagnosis of　ADTKD-UMOD. Considering the stability of the procedure, serum UMOD may be more reliable than urinary UMOD measurement.

The glycoprotein uromodulin (UMOD) is the most abundant protein in human urine and forms filamentous homopolymers that encapsulate and aggregate uropathogens, promoting pathogen clearance by urine excretion. Despite its critical role in the innate immune response against urinary tract infections, the structural basis and mechanism of UMOD polymerization remained unknown. Here, we present the cryo-EM structure of the UMOD filament core at 3.5 Å resolution, comprised of the bipartite zona pellucida (ZP) module in a helical arrangement with a rise of ~65 Å and a twist of ~180°. The immunoglobulin-like ZPN and ZPC subdomains of each monomer are separated by a long linker that interacts with the preceding ZPC and following ZPN subdomains by β-sheet complementation. The unique filament architecture suggests an assembly mechanism in which subunit incorporation could be synchronized with proteolytic cleavage of the C-terminal pro-peptide that anchors assembly-incompetent UMOD precursors to the membrane.

Uromodulin (also known as Tamm–Horsfall protein) is a kidney-specific glycoprotein secreted bidirectionally into urine and into the circulation, and it is the most abundant protein in normal urine. Although the discovery of uromodulin predates modern medicine, its significance in health and disease has been rather enigmatic. Research studies have gradually revealed that uromodulin exists in multiple forms and has important roles in urinary and systemic homeostasis. Most uromodulin in urine is polymerized into highly organized filaments, whereas non-polymeric uromodulin is detected both in urine and in the circulation, and can have distinct roles. The interactions of uromodulin with the immune system, which were initially reported to be a key role of this protein, are now better understood. Moreover, the discovery that uromodulin is associated with a spectrum of kidney diseases, including acute kidney injury, chronic kidney disease and autosomal-dominant tubulointerstitial kidney disease, has further accelerated investigations into the role of this protein. These discoveries have prompted new questions and ushered in a new era in uromodulin research. Here, we delineate the latest discoveries in uromodulin biology and its emerging roles in modulating kidney and systemic diseases, and consider future directions, including its potential clinical applications.In this Review, the authors examine advances in uromodulin biology, including the existence of non-polymeric forms of the protein, its versatile functions, crosstalk with the immune system, its potential as a biomarker and its role in kidney disease, as well as considering how uromodulin might be targeted therapeutically.

Uromodulin is the most abundant protein in human urine, playing diverse roles, from providing frontline defense against uropathogens to regulating electrolyte balance via modulation of ion channels and cotransporters. In this issue of the JCI , Nanamatsu et al. unveil an alternatively spliced isoform of uromodulin that was dynamically induced in response to oxidative stress and tubular injury. Unlike the canonical secreted form, this isoform was retained in the cell, where it interacted with solute carrier proteins primarily localized to the mitochondrial membrane. Through these interactions, it modulated mitochondrial energetics and enhanced tubular cell resilience to injury. These findings broaden our understanding of uromodulin’s multifaceted functions, uncover an adaptive mechanism by which the kidney responds to cellular stress, and open avenues for therapeutic strategies targeting kidney injury and repair.

The most abundant urinary protein, Tamm–Horsfall protein, later renamed uromodulin, is expressed exclusively by the thick ascending limb cells of the kidney and released into urine from the apical cell membrane. Uromodulin is believed to protect against urinary tract infections and stones, but its other physiologic functions have remained obscure until recently. Renewed interest in uromodulin has been brought about by the identification of uromodulin mutations as causes of a discrete group of diseases that are distinct from nephronophthisis. The three overlapping clinical uromodulin-associated kidney diseases (UAKD) are medullary cystic disease type 2, familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Previously thought of as \"adult diseases\", it is now recognized that they may also present in childhood and even in infancy. Common characteristics of all three diseases are autosomal dominant inheritance, unremarkable urine sediment and slow progression to end-stage renal disease (ESRD). They are frequently associated with hyperuricemia and gout. These diseases appear to result from failure of the mutant uromodulin to be incorporated into the apical cilium, thereby placing UAKD in the category of \"ciliopathies\". In addition to causing specific UAKD, certain uromodulin gene polymorphisms have been linked to ESRD in general, suggesting that uromodulin plays a modulatory role in kidney disease progression.

Glycoprotein 2 (GP2) and uromodulin (UMOD) filaments protect against gastrointestinal and urinary tract infections by acting as decoys for bacterial fimbrial lectin FimH. By combining AlphaFold2 predictions with X-ray crystallography and cryo-EM, we show that these proteins contain a bipartite decoy module whose new fold presents the high-mannose glycan recognized by FimH. The structure rationalizes UMOD mutations associated with kidney diseases and visualizes a key epitope implicated in cast nephropathy. AlphaFold2 predictions, X-ray crystallography and cryo-EM analyses reveal how related human glycoproteins GP2 and uromodulin catch pathogenic bacteria by presenting a high-mannose glycan that acts as a decoy for fimbrial adhesin FimH.

Background Uromodulin has been speculated as a protective factor for acute kidney injury (AKI) and chronic kidney disease (CKD), possibly based on the uromodulin-mediated cross-talk between thick ascending limbs and proximal tubules. Here, we explored the roles of uromodulin in the AKI-CKD transition. Methods Wild-type SD rats and UMOD −/− rats were subjected to the AKI-CKD transition models. Cisplatin-stimulated HK-2 cells were treated with or without uromodulin. The renal injury and cell damage were evaluated. Results UMOD −/− rats observed no spontaneous kidney injury and fibrosis. In two rat models of AKI-CKD transition, induced by repeated cisplatin nephrotoxicity and ischemia-reperfusion injury, UMOD deficiency exacerbated the kidney insufficiency and fibrosis along with the over-activation of EGFR signaling. In the kidneys treated with cisplatin repeatedly, immunofluorescence showed the translocation of uromodulin and its proximity to EGFR and coimmunoprecipitation experiments also verified their interaction. Molecular docking and microscale thermophoresis demonstrated a significant binding capacity of EGFR with uromodulin and its EGF-like domains. Supplying uromodulin to cisplatin-stimulated HK-2 cells decreased the fibrotic process and the EGFR abundance, associated with the elevated EGFR ubiquitylation. Recombinant EGF-like domains of uromodulin showed a similar binding capacity and EGFR suppression effect with uromodulin. Uromodulin-induced EGFR endocytosis was impaired by the EGFR kinase inhibitor or monoclonal antibody. Conclusions Collectively, we discovered uromodulin may alleviate the progression of AKI-CKD transition via the EGFR suppression.

Key Points Uromodulin — the most abundant urinary protein — is exclusively produced by renal epithelial cells; in the tubular lumen uromodulin forms high-molecular weight filaments that constitute the matrix of hyaline casts Important functions of uromodulin include regulation of ion transport in the thick ascending limb, immunomodulation and protection against urinary tract infections and kidney stones Levels of uromodulin in the urine and in the blood, where it is present in lower amounts, are valuable biomarkers for tubular mass and renal function Rare mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease; these mutations lead to retention of mutant uromodulin in the endoplasmic reticulum of tubular cells, tubulointerstitial damage and decreased levels of urinary uromodulin Common variants in the UMOD promoter are associated with risk of chronic kidney disease (CKD) and hypertension; the unusually high prevalence of UMOD risk alleles suggests pathogen-driven selective pressure UMOD represents a paradigm as a continuum of genetic disease risk, from rare mutations in Mendelian disease to common variants associated with complex traits including CKD and hypertension Uromodulin is the most abundant urinary protein. Here, the authors discuss the physiological roles of uromodulin, the mechanisms by which mutations in the UMOD gene, which encodes uromodulin, cause autosomal dominant tubulointerstitial kidney disease and the association of common UMOD variants with complex disorders in the general population. Uromodulin (also known as Tamm-Horsfall protein) is exclusively produced in the kidney and is the most abundant protein in normal urine. The function of uromodulin remains elusive, but the available data suggest that this protein might regulate salt transport, protect against urinary tract infection and kidney stones, and have roles in kidney injury and innate immunity. Interest in uromodulin was boosted by genetic studies that reported involvement of the UMOD gene, which encodes uromodulin, in a spectrum of rare and common kidney diseases. Rare mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), which leads to chronic kidney disease (CKD). Moreover, genome-wide association studies have identified common variants in UMOD that are strongly associated with risk of CKD and also with hypertension and kidney stones in the general population. These findings have opened up a new field of kidney research. In this Review we summarize biochemical, physiological, genetic and pathological insights into the roles of uromodulin; the mechanisms by which UMOD mutations cause ADTKD, and the association of common UMOD variants with complex disorders.