Uromodulin in kidney injury: an instigator, bystander, or protector?

Abstract

Uromodulin, also known as Tamm-Horsfall protein, is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. Although the physiologic functions of this protein remain elusive, significant progress has been made during the last decade that highlights the importance of uromodulin in the pathophysiology of various diseases, such as medullary cystic kidney disease, urinary tract infections, and nephrolithiasis. Meanwhile, there is renewed interest in the role of uromodulin in kidney injury, both acute and chronic. In this article, we review the existing evidence that supports a role for uromodulin in acute kidney injury, chronic kidney disease, and renal inflammation. Contrary to the conventional view of uromodulin as an instigator in kidney injury, new data from uromodulin knockout mice show a protective role for this protein in acute kidney injury, possibly through downregulating interstitial inflammation. In chronic kidney disease, uromodulin excretion, when adjusted for kidney function, is increased; the significance of this is unclear. Although it has been suggested that uromodulin exacerbates progressive kidney injury, we propose that the elevation in uromodulin secretion is instead reactive to injury and reflects an increase of uromodulin in the renal parenchyma, where it slows the injury process.

Figure 1. Conceptual model of the uromodulin-dependent protective cross-talk in Acute Kidney Injury (AKI)

This figure represents a cross-section of the outer medulla, where thick ascending limb (TAL), and S3 segments of the proximal tubules are contiguous. During AKI, S3 segments are predominantly injured, and express several pro-inflammatory factors. Path 1 illustrates a direct role of basolateral released uromodulin in down-regulating inflammatory signaling in neighboring S3 segments. Path 2 shows the possibility of a secondary paracrine mediator, released by the TAL in a uromodulin-dependent process with the net effect of protecting neighboring tubule. Path 3 shows a possible “hybrid” mechanism, whereby the protective effect of uromodulin depends on its interaction with an interstitial cell (IC), which in turn regulates or inhibits inflammatory signaling in S3 segments.

Figure 2. Measurement of urinary uromodulin in the form of an index

The interpretation of this index depends on the clinical context: no kidney disease, at risk for kidney disease, and established disease. In patients with normal kidney function and no risk factors for kidney disease, a low index could suggest susceptibility to acute kidney injury (AKI) (reference 34). In patients with established risk factors for chronic kidney disease (CKD), such as diabetes mellitus, a high index could be reactive to subtle injury, and thereby predict the development of CKD (reference 85). In patients with established CKD, a high index could signal ongoing injury and further progression. However, in very advanced disease, a low index could imply depletion of tubular reserves and progression to end-stage. Abbreviations: GFR, glomerular filtration rate.

Figure 3. Possible mechanisms whereby uromodulin can modulate chronic injury

(A) a possible role of apical uromodulin in maintaining the integrity of the thick ascending limb (TAL) by forming a protective layer at the apex of TAL. Uromodulin may also regulate the function of some ion channels and transporters (references –8, 84). If injury affects the normal sorting or function of uromodulin at the apical membrane, a breach of TAL integrity and significant electrolyte dysregulation can occur. Panel B illustrates a pro-inflammatory role of uromodulin. Chronic injury can lead to increased basolateral/interstitial uromodulin (1). In this location, uromodulin can stimulate inflammatory signaling (2) through an immunologic response, thereby aggravating injury (3) and promoting subsequent fibrosis. Panel C shows the possibility that uromodulin has a protective role in chronic injury. A persistent inflammatory response during chronic injury (1) can stimulate the release of basolateral/interstitial uromodulin (2). This reactive increase of uromodulin in the interstitium serves to counter the inflammatory response and limit its progression (3). Supportive data for this model are derived from acute injury experiments on uromodulin knockout mice.