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

Abstract

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.

Keywords: Tamm-Horsfall Protein; hypertension; kidney injury; renal physiology; uromodulin.

Figure 1:. Primary structure of Uromodulin and three-dimensional model from Alphafold database

(A) Schematic of uromodulin domains and cleavage sites. SP, signal peptide; I, II, III, and IV, EGF domains; D8C, cysteine-rich domain; ZP, zona pellucida domain; GPI, glycosylphosphatidylinositol anchor at 614; CCS, consensus cleavage site at 587; IHP, internal hydrophobic patch (430–436 and 456–462); EHP, external hydrophobic patch (598–607). (B) 3D protein structure model of uromodulin (AlphaFold) precursor using with domains labeled and color corresponding to (A).

Figure 2:. Pathways for Uromodulin release in the urine and circulation.

Polymerizing uromodulin is targeted towards the apical membrane, where it is GPI anchored (inset). It is cleaved by hepsin at the consensus cleavage site, which releases the inhibitory external hydrophobic patch (EHP) site, thereby inducing conformational changes that allow the zona pellucida domains to polymerize. Non-polymerizing uromodulin is not cleaved by hepsin and is released in the urine without GPI anchoring. Non-polymerizing uromodulin is also the main form released from the basolateral domain to the kidney interstium and circulation

Figure 3:. Expression of Uromodulin in mouse and Human kidney by large-scale confocal immunofluorescence imaging.

(A) large scale confocal fluorescence imaging of a mouse kidney showing the distribution of uromodulin. The density of thick ascending limbs in the inner stripe increases the abundance of uromodulin in this specific renal zone. (B) Large scale imaging of a human nephrectomy tissue specimen showing the distribution of uromodulin in the cortex and upper medulla.

Figure 4:. Role of polymerizing and non-polymerizing uromodulin in context of site of action.

These functions are based on a summary of the literature in experimental and clinical setting. The role of uromodulin likely depends on the form and abundance of uromodulin, the site of interaction and the cell type(s) involved. Thick ascending limb, TAL; Distal convoluted tubule (DCT); Connecting tubule (CNT).