Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation

Lan Mo, Hong Ying Huang, Xin Hua Zhu, Ellen Shapiro, David L. Hasty, Xue Ru Wu

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1159-1166
Number of pages8
JournalKidney International
Volume66
Issue number3
DOIs
StatePublished - Sep 2004
Externally publishedYes

Fingerprint

Uromodulin
Calcium Oxalate
Kidney
Calcium
Osteopontin
Crystallization
Polarization Microscopy
Vascular Calcification
Physiologic Calcification
Nephrolithiasis
Oxalates
Ethylene Glycol
Cholecalciferol
Knockout Mice
Electron Scanning Microscopy
Minerals
Coloring Agents
Salts
Epithelial Cells

Keywords

  • Calcium oxalate stones
  • Knockout
  • Macromolecules
  • Nephrolithiasis
  • Osteopontin
  • Tamm-Horsfall protein
  • Uromodulin

ASJC Scopus subject areas

  • Nephrology

Cite this

Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. / Mo, Lan; Huang, Hong Ying; Zhu, Xin Hua; Shapiro, Ellen; Hasty, David L.; Wu, Xue Ru.

In: Kidney International, Vol. 66, No. 3, 09.2004, p. 1159-1166.

Research output: Contribution to journalArticle

Mo, Lan ; Huang, Hong Ying ; Zhu, Xin Hua ; Shapiro, Ellen ; Hasty, David L. ; Wu, Xue Ru. / Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. In: Kidney International. 2004 ; Vol. 66, No. 3. pp. 1159-1166.
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AU - Wu, Xue Ru

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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.

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