The importance of uromodulin as regulator of salt reabsorption along the thick ascending limb.

Uromodulin (UMOD), also named Tamm Horsfall protein, is the most abundant protein secreted in the urine under normal conditions. It was purified the first time in 1950 and since then considerable efforts have highlighted its importance in human pathophysiology. However, its precise biological functions still remain elusive. The clinical interest in UMOD derives from the evidence that UMOD genetic mutations result in tubulointerstitial nephropathies currently known as UMODassociated kidney disease (UAKD), rare genetic disorders characterized by hyperuricaemia, gout and a progressive decline of renal function [1]. In addition, UMOD has been proposed to modulate water and electrolyte homeostasis by acting on the main transporters expressed along the thick ascending limb (TAL) and the early distal convoluted tubule. The precursor undergoes extensive post-translational modifications through the endoplasmic reticulum (ER) and the Golgi apparatus, and ultimately it is targeted to the apical membrane [2]. From the luminal site, it is cleaved by an unknown protease and then released into the tubular fluid. The exact mechanism linking UMOD mutations to renal concentrating defect has not been fully characterized. It has been suggested that the filamentous gel-like structure of the extracellular domain may serve as a barrier to water permeability [3]. In vitro and in vivo studies have recently demonstrated that UMOD modulates the function of the Na-K-2Cl (NKCC2) co-transporter [4] and the renal outer medullary potassium (ROMK) channel [5] (Figure 1). UMOD-deficient mice showed normal electrolyte balance at basal and urine concentrating defect after water deprivation [6]. Impaired urine concentration was coupled with a compensatory up-regulation of distal Na transporters, including the Na-Cl co-transporter (NCC), suggesting indirectly an impaired function of the TAL. Immunostaining analysis revealed the absence of any difference in NKCC2 protein abundance on the apical membrane between knockout (KO) and wild-type (WT) mice, but an increased sub-apical immunoreactivity, with overall increased NKCC2 protein abundance compared with WT [4]. It is possible that an impaired protein degradation, in the absence of UMOD, resulted in NKCC2 accumulation. However, the same study demonstrated that phospho-NKCC2 levels, a marker of NKCC2 activity, were lower in KO than WT mice, and intraperitoneal injection of frusemide resulted in attenuated natriuretic and cloruretic responses, further supporting the hypothesis of reduced NKCC2 activity in the absence of UMOD. Consistent with these findings, in vitro NKCC2 phosphorylation was enhanced in the presence of UMOD, indicating that also in cultured cells UMOD promoted NKCC2 activity. This hypothesis has been further corroborated by recent observations linking salt-sensitive hypertension with a genetic UMOD variant leading to an increased UMOD synthesis and secretion in humans [7]. Transgenic mice expressing this genetic variant resembled human features, showing salt-sensitive hypertension. This finding correlated with the up-regulation of NKCC2, with increased protein phosphorylation via the STE20/SPS1-related proline/alanine-rich kinase (SPAK) and the down-regulation of the negative regulator kidney-specific KS-SPAK. Besides NKCC2, UMOD has been shown to modulate also the activity of ROMK. Renigunta et al. [5] have shown that UMOD co-localized with ROMK in a protein lysate from mice, while in oocytes, co-expression of UMOD and ROMK resulted in increased current amplitude, associated with an increased surface ROMK abundance. Patients suffering from UAKD commonly do manifest a defect in urine concentrating ability even before the decline of the GFR [8]. The mechanism by which UMOD mutations lead to urine concentrating defect in humans remains to be better elucidated. In this issue of NDT, Labriola et al. [9] show original data exploring the tubular function of a patient suffering UAKD during the early phase of the disease.