NH4Cl treatment prevents tissue calcification in klotho deficiency

Christina B. Leibrock, Ioana Alesutan, Jakob Voelkl, Tatsiana Pakladok, Diana Michael, Erwin Schleicher, Zahra Kamyabi-Moghaddam, Leticia Quintanilla-Martinez, Makoto Kuro-O, Florian Lang

Research output: Contribution to journalArticle

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Abstract

Klotho, a cofactor in suppressing 1,25(OH)2D3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH)2D3, Ca2+, and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescenceassociated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH4Cl treatment in drinking water (0.28 M) prevented soft tissue and vascular calcification and increased the life span of kl/kl mice .>12-fold in males and >4-fold in females without significantly affecting extracellular pH or plasma concentrations of 1,25(OH)2D3, Ca2+, and phosphate. NH4Cl treatment significantly decreased plasma aldosterone and antidiuretic hormone concentrations and reversed the increase of Runx2/Cbfa1, Alpl, Tgfb1, Pai-1, p21, and Glb1 expression in aorta of kl/kl mice. Similarly, in primary human aortic smooth muscle cells (HAoSMCs), NH4Cl treatment reduced phosphate-induced mRNA expression of RUNX2/CBFA1, ALPL, and senescence-associated molecules. In both kl/kl mice and phosphate-treated HAoSMCs, levels of osmosensitive transcription factor NFAT5 and NFAT5-downstream mediator SOX9 were higher than in controls and decreased after NH4Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH4Cl on SOX9, RUNX2/CBFA1, and ALPL mRNA expression. TGFB1 treatment of HAoSMCs upregulated NFAT5 expression and prevented the decrease of phosphate-induced NFAT5 expression after NH4Cl treatment. In conclusion, NH4Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH4Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5- dependent osteochondrogenic signaling.

Original languageEnglish (US)
Pages (from-to)2423-2433
Number of pages11
JournalJournal of the American Society of Nephrology
Volume26
Issue number10
DOIs
StatePublished - Oct 1 2015

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Phosphates
Smooth Muscle Myocytes
Vascular Calcification
Transcription Factors
Messenger RNA
Hyperaldosteronism
Aldosterone
Vasopressins
Drinking Water
Minerals
Blood Vessels
Aorta

ASJC Scopus subject areas

  • Nephrology

Cite this

Leibrock, C. B., Alesutan, I., Voelkl, J., Pakladok, T., Michael, D., Schleicher, E., ... Lang, F. (2015). NH4Cl treatment prevents tissue calcification in klotho deficiency. Journal of the American Society of Nephrology, 26(10), 2423-2433. https://doi.org/10.1681/ASN.2014030230

NH4Cl treatment prevents tissue calcification in klotho deficiency. / Leibrock, Christina B.; Alesutan, Ioana; Voelkl, Jakob; Pakladok, Tatsiana; Michael, Diana; Schleicher, Erwin; Kamyabi-Moghaddam, Zahra; Quintanilla-Martinez, Leticia; Kuro-O, Makoto; Lang, Florian.

In: Journal of the American Society of Nephrology, Vol. 26, No. 10, 01.10.2015, p. 2423-2433.

Research output: Contribution to journalArticle

Leibrock, CB, Alesutan, I, Voelkl, J, Pakladok, T, Michael, D, Schleicher, E, Kamyabi-Moghaddam, Z, Quintanilla-Martinez, L, Kuro-O, M & Lang, F 2015, 'NH4Cl treatment prevents tissue calcification in klotho deficiency', Journal of the American Society of Nephrology, vol. 26, no. 10, pp. 2423-2433. https://doi.org/10.1681/ASN.2014030230
Leibrock CB, Alesutan I, Voelkl J, Pakladok T, Michael D, Schleicher E et al. NH4Cl treatment prevents tissue calcification in klotho deficiency. Journal of the American Society of Nephrology. 2015 Oct 1;26(10):2423-2433. https://doi.org/10.1681/ASN.2014030230
Leibrock, Christina B. ; Alesutan, Ioana ; Voelkl, Jakob ; Pakladok, Tatsiana ; Michael, Diana ; Schleicher, Erwin ; Kamyabi-Moghaddam, Zahra ; Quintanilla-Martinez, Leticia ; Kuro-O, Makoto ; Lang, Florian. / NH4Cl treatment prevents tissue calcification in klotho deficiency. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 10. pp. 2423-2433.
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AU - Kamyabi-Moghaddam, Zahra

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N2 - Klotho, a cofactor in suppressing 1,25(OH)2D3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH)2D3, Ca2+, and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescenceassociated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH4Cl treatment in drinking water (0.28 M) prevented soft tissue and vascular calcification and increased the life span of kl/kl mice .>12-fold in males and >4-fold in females without significantly affecting extracellular pH or plasma concentrations of 1,25(OH)2D3, Ca2+, and phosphate. NH4Cl treatment significantly decreased plasma aldosterone and antidiuretic hormone concentrations and reversed the increase of Runx2/Cbfa1, Alpl, Tgfb1, Pai-1, p21, and Glb1 expression in aorta of kl/kl mice. Similarly, in primary human aortic smooth muscle cells (HAoSMCs), NH4Cl treatment reduced phosphate-induced mRNA expression of RUNX2/CBFA1, ALPL, and senescence-associated molecules. In both kl/kl mice and phosphate-treated HAoSMCs, levels of osmosensitive transcription factor NFAT5 and NFAT5-downstream mediator SOX9 were higher than in controls and decreased after NH4Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH4Cl on SOX9, RUNX2/CBFA1, and ALPL mRNA expression. TGFB1 treatment of HAoSMCs upregulated NFAT5 expression and prevented the decrease of phosphate-induced NFAT5 expression after NH4Cl treatment. In conclusion, NH4Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH4Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5- dependent osteochondrogenic signaling.

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