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1 Department of Anatomy, Medical Faculty of the Charite, Berlin, Germany
2 the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
3 Nephrology/Hypertension at the Franz Volhard Clinic-HELIOS Clinics and Max Delbruck Center for Molecular Medicine, Medical Faculty of the Charite, Berlin, Germany
4 Department of Physiology, Medical Faculty of the Charite, Berlin, Germany
* To whom correspondence should be addressed. E-mail: sbachm{at}charite.de.
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 to wild type (wt) mice. THP -/- displayed anatomically normal kidneys. Steady state electrolyte handling was not different between strains. Creatinine clearance was 63% lower in THP -/- than in wt (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 µl/g bw/24 h in wt mice (p<0.05), whereas in THP -/- mice this decrease was less pronounced (57±4 to 41±5 µl/g bw/24 h; p<0.05), revealing significant inter-strain 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 to 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, while 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.
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