TY - JOUR
T1 - Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation
AU - Mo, Lan
AU - Huang, Hong Ying
AU - Zhu, Xin Hua
AU - Shapiro, Ellen
AU - Hasty, David L.
AU - Wu, Xue Ru
N1 - Funding Information:
This work was supported in part by grants from National Institutes of Health (DK56903) to X.-R. Wu, (AI42886) to D.L. Hasty, and a Merit Review award from the Veterans Administration's Medical Research Service to X.-R. Wu.
PY - 2004/9
Y1 - 2004/9
N2 - 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 D3, 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. Conclusion. 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.
AB - 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 D3, 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. Conclusion. 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.
KW - Calcium oxalate stones
KW - Knockout
KW - Macromolecules
KW - Nephrolithiasis
KW - Osteopontin
KW - Tamm-Horsfall protein
KW - Uromodulin
UR - http://www.scopus.com/inward/record.url?scp=4344664015&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4344664015&partnerID=8YFLogxK
U2 - 10.1111/j.1523-1755.2004.00867.x
DO - 10.1111/j.1523-1755.2004.00867.x
M3 - Article
C2 - 15327412
AN - SCOPUS:4344664015
SN - 0085-2538
VL - 66
SP - 1159
EP - 1166
JO - Kidney international
JF - Kidney international
IS - 3
ER -