ArticleJournal of the American Society of Nephrology : JASN2015
NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency.
Article in Journal of the American Society of Nephrology : JASN, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 61 citations in OpenAlex.
- The effects of elevated phosphate on the kidney - damaging the gatekeeper.Pflugers Archiv : European journal of physiology · 2026Review
- Soft tissue accumulations of phosphate are not always associated with serum phosphate or with calcifications in mouse models of hyperphosphatemia.The Journal of physiology · 2025Article
- Soft tissue calcifications in chronic kidney disease-beyond the vasculature.Pflugers Archiv : European journal of physiology · 2025Review
- Elevated phosphate levels in CKD - a direct threat for the heart.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025Review
- Fisetin ameliorates vascular smooth muscle cell calcification via DUSP1-dependent p38 MAPK inhibition.Aging · 2025Article
- Rel Family Transcription Factor NFAT5 Upregulates COX2 via HIF-1α Activity in Ishikawa and HEC1a Cells.International journal of molecular sciences · 2024Article
- Similarities and Differences of Vascular Calcification in Diabetes and Chronic Kidney Disease.Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- Signaling pathways in vascular function and hypertension: molecular mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2023Review
- Cholecalciferol supplementation effectively improved tertiary hyperparathyroidism, FGF23 resistance and lowered coronary calcification score: a prospective study.Endocrine connections · 2022Article
- Bone marrow mesenchymal stem cell-derived exosomal microRNA-381-3p alleviates vascular calcification in chronic kidney disease by targeting NFAT5.Cell death & disease · 2022Article
- Oral Acid Load Down-Regulates Fibroblast Growth Factor 23.Nutrients · 2022Article
- Review
- Impact of Ninjin'yoeito on frailty and short life in klotho-hypomorphic (kl/kl) mice.Frontiers in pharmacology · 2022Article
- Increased TGFβ1 and SMAD3 Contribute to Age-Related Aortic Valve Calcification.Frontiers in cardiovascular medicine · 2022Article
- Phosphate Is a Cardiovascular Toxin.Advances in experimental medicine and biology · 2022Review
- Effect of MgClInternational journal of molecular sciences · 2021Article
- Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p.Communications biology · 2020Article
- Review
- Beta-Glycerophosphate-Induced ORAI1 Expression and Store Operated CaScientific reports · 2020Article
- Phosphate-induced ORAI1 expression and store-operated CaJournal of molecular medicine (Berlin, Germany) · 2019Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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, Ca(2+), 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 senescence-associated 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, Ca(2+), 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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