Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice

Abstract

The Tamm-Horsfall protein (THP; uromodulin), the dominant protein in normal urine, is produced exclusively in the thick ascending limb of Henle's loop. THP mutations are associated with disease; however, the physiological role of THP remains obscure. We generated THP gene-deficient mice (THP -/-) and compared them with wild-type (WT) mice. THP -/- mice displayed anatomically normal kidneys. Steady-state electrolyte handling was not different between strains. Creatinine clearance was 63% lower in THP -/- than in WT mice (P < 0.05). Sucrose loading induced no changes between strains. However, water deprivation for 24 h decreased urine volume from 58 +/- 9 to 28 +/- 4 microl x g body wt(-1) x 24 h(-1) in WT mice (P < 0.05), whereas in THP -/- mice this decrease was less pronounced (57 +/- 4 to 41 +/- 5 microl x g body wt(-1) x 24 h(-1); P < 0.05), revealing significant interstrain difference (P < 0.05). We further used RT-PCR, Northern and Western blotting, and histochemistry to study renal transporters, channels, and regulatory systems under steady-state conditions. We found that major distal transporters were upregulated in THP -/- mice, whereas juxtaglomerular immunoreactive cyclooxygenase-2 (COX-2) and renin mRNA expression were both decreased in THP -/- compared with WT mice. These observations suggest that THP influences transporters in Henle's loop. The decreased COX-2 and renin levels may be related to an altered tubular salt load at the macula densa, whereas the increased expression of distal transporters may reflect compensatory mechanisms. Our data raise the hypothesis that THP plays an important regulatory role in the kidney.

Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion

“…Of note, uromodulin knockout mice display a reduced NKCC2 cotransporter phosphorylation, whereas overexpression of uromodulin in vitro increases NKCC2 phosphorylation (11). Furthermore, uromodulin increases the activity of ROMK, which supports the view that it modulates NKCC2-dependent NaCl reabsorption in the TAL (12,32,33). In view of its exclusive distribution in the TAL, uromodulin is a priori unrelated to the proximal tubule, where urate is principally handled.…”

Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population

“…The positive association between uromodulin and urinary osmolality is of interest because the latter parameter also reflects TAL activity. A potential role of uromodulin in osmoregulation has been suggested by mouse studies: For example, Umod knockout mice show NaCl wasting and impaired urinary concentration (3).…”

“…Uromodulin is exclusively synthesized by the epithelial cells lining the thick ascending limb (TAL) of the loop of Henle, where it is sorted to the apical plasma membrane and released into the tubular lumen by proteolytic cleavage (2). The biologic role of uromodulin is emerging, with studies in knockout mice showing that it regulates NaCl transport processes operating in the TAL (3,4).…”

Deletion of von Hippel–Lindau Protein Converts Renin-Producing Cells into Erythropoietin-Producing Cells

“…54 Digoxygenin-labeled UTP and T7 or SP6 RNA polymerase (Roche Applied Science, Mannheim, Germany) were used to generate sense and antisense RNA probes. In situ hybridization was performed as previously described, 55,56 and hybridized RNA probes were visualized using 4-nitroblue tetrazolium chloride. Sections were examined using a Leica DMRB microscope equipped with an interference contrast module (Leica, Wetzlar, Germany).…”