Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation.
BACKGROUND
The tubular fluid of the mammalian kidney is often supersaturated with mineral salts, but crystallization rarely occurs under normal conditions. The unique ability of the kidney to avoid harmful crystal formation has long been attributed to the inhibitory activity of the urinary macromolecules, although few in vivo studies have been carried out to examine this hypothesis. Here we examined the role of Tamm-Horsfall protein (THP), the principal urinary protein, in urinary defense against renal calcium crystal formation, using a THP knockout model that we recently developed.


METHODS
Wild-type and THP knockout mice were examined for the spontaneous formation of renal calcium crystals using von Kossa staining. The susceptibility of these mice to experimentally induced renal crystal formation was evaluated by administering mice with ethylene glycol, a precursor of oxalate, and vitamin D(3), which increases calcium absorption. Renal calcium crystals were visualized by von Kossa stain, dark field microscopy with polarized light and scanning electron microscopy.


RESULTS
Inactivating the THP gene in mouse embryonic stem cells results in spontaneous formation of calcium crystals in adult kidneys. Excessive intake of calcium and oxalate, precursors of the most common type of human renal stones, dramatically increases both the frequency and the severity of renal calcium crystal formation in THP-deficient, but not in wild-type mice. Under high calcium/oxalate conditions, the absence of THP triggers a marked, adaptive induction in renal epithelial cells of osteopontin (OPN), a potent inhibitor of bone mineralization and vascular calcification. Thus, OPN may serve as an inducible inhibitor of calcium crystallization, whereas THP can serve as a constitutive and apparently more effective inhibitor.


CONCLUSIONS
These results provide the first in vivo evidence that THP is a critical urinary defense factor and suggest that its deficiency could be an important contributing factor in human nephrolithiasis, a condition afflicting tens of millions of people in the world annually.
Department of Urology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10010, USA.
Lan
L
Mo
Hong-Ying
HY
Huang
Xin-Hua
XH
Zhu
Ellen
E
Shapiro
David L
DL
Hasty
Xue-Ru
XR
Wu
D000818:Animals; D002129:Calcium Oxalate / Q000737:chemistry* / Q000652:urine*; D003460:Crystallization; D020022:Genetic Predisposition to Disease; D007668:Kidney / Q000502:physiology; D007669:Kidney Calculi / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009088:Mucoproteins / Q000235:genetics* / Q000652:urine*; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D058949:Uromodulin
D009088:Mucoproteins; D012333:RNA, Messenger; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin; D053495:Osteopontin; D002129:Calcium Oxalate