Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice.
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.
Bachmann
Sebastian
S
Medical Faculty of the Charité, Department of Anatomy, Franz Volhard Clinic, HELIOS Clinics and Max Delbrück Center for Molecular Medicine, Berlin, Germany. sbachm@charite.de
Mutig
Kerim
K
Bates
James
J
Welker
Pia
P
Geist
Beate
B
Gross
Volkmar
V
Luft
Friedrich C
FC
Alenina
Natalia
N
Bader
Michael
M
Thiele
Bernd J
BJ
Prasadan
Krishna
K
Raffi
Hajamohideen S
HS
Kumar
Satish
S
D000818:Animals; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D051546:Cyclooxygenase 2; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007606:Juxtaglomerular Apparatus / Q000378:metabolism; D007668:Kidney / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009088:Mucoproteins / Q000172:deficiency*; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009399:Nephrons / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058949:Uromodulin; D014882:Water-Electrolyte Balance / Q000235:genetics / Q000502:physiology
D002352:Carrier Proteins; D009088:Mucoproteins; C548613:Umod protein, mouse; D058949:Uromodulin; D003404:Creatinine; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D009252:NADPH Dehydrogenase; D012083:Renin