Lysosomotropic drugs inhibit maturation of transforming growth factor-β

Basque, Julie; Martel, Marc; Leduc, Richard; Cantin, André M.

doi:10.1139/y08-063

Cited by 33 publications

(25 citation statements)

References 29 publications

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“…NH 4 Cl has previously been shown to hinder the maturation of Tgfb1. 51 According to our observations, expression of Nfat5 and Sox9 is upregulated in kl/kl mice and decreased by NH 4 Cl treatment. NFAT5 in turn upregulates the transcript levels of CBFA1 and ALPL.…”

Section: Discussionmentioning

confidence: 56%

“…[45][46][47] Cell swelling downregulates the cell volume-sensitive transcription factor Tonicity-Responsive Enhancer Binding Protein or nuclear factor of activated T cells (NFAT5), 48,49 which has been implicated in the regulation of Cbfa1 expression, a function involving the transcription factor Sox9. 50 Beyond that, lysosomal alkalinization prevents maturation of several proteins including TGFB1, 51 which in turn is known to upregulate NFAT5 52 and participate in osteogenic signaling. [53][54][55][56] This study explored the effect of NH 4 Cl treatment on the phenotype of klotho-hypomorphic mice.…”

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confidence: 99%

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NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Leibrock¹,

Alesutan²,

Voelkl³

et al. 2015

Journal of the American Society of Nephrology

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Klotho, a cofactor in suppressing 1,25(OH) 2 D 3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH) 2 D 3 , 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 senescenceassociated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH 4 Cl 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) 2 D 3 , Ca 2+ , and phosphate. NH 4 Cl 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), NH 4 Cl 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 NH 4 Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH 4 Cl 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 NH 4 Cl treatment. In conclusion, NH 4 Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH 4 Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5-dependent osteochondrogenic signaling.

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Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 99%

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Leibrock¹,

Alesutan²,

Voelkl³

et al. 2015

Journal of the American Society of Nephrology

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“…Alkalinization of acidic cellular compartments has previously been shown to impede the maturation of TGFß1, an effect presumably due to inhibition of pH-sensitive luminal enzymes [30]. Impaired acidification of endosomes could further disrupt receptor/ligand dissociation and interfere with TGFß1 receptor externalization [40,41].…”

Section: Discussionmentioning

confidence: 99%

“…In acidic compartments, NH 3 binds H + and is thus trapped as NH 4 + [29]. As a result, NH 4 Cl alkalinizes acidic cellular compartments, which is known to prevent maturation of several proteins including TGFß1 [30]. It was thus hypothesized that NH 4 + is effective by alkalinizing acidic cellular compartments.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Phosphate-Induced Vascular Smooth Muscle Cell Osteo-/Chondrogenic Signaling and Calcification by Bafilomycin A1 and Methylamine

Alesutan

Musculus

Castor

et al. 2015

Kidney Blood Press Res

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Background/Aims: Excessive phosphate concentrations trigger vascular calcification, an active process promoted by osteoinduction of vascular smooth muscle cells (VSMCs) with increased expression and activity of transcription factor RUNX2 (Core-binding factor α1, CBFA1), alkaline phosphatase (ALPL), TGFß1, transcription factor NFAT5, and NFAT5-sensitive transcription factor SOX9. The osteoinductive signaling and vascular calcification of hyperphosphatemic klotho-hypomorphic mice could be reversed by treatment with NH₄Cl, effects involving decrease of TGFß1 and inhibition of NFAT5-dependent osteoinductive signaling. Known effects of NH₄Cl include alkalinization of acidic cellular compartments. The present study explored whether osteo-/chondrogenic signaling could be influenced by alkalinization of acidic cellular compartments following inhibition of the vacuolar H⁺ ATPase with bafilomycin A1 or following dissipation of the pH gradient across the membranes of acidic cellular compartments with methylamine. Methods: Primary human aortic smooth muscle cells (HAoSMCs) were treated with high phosphate to trigger osteo-/chondrogenic signaling and calcification in the absence or presence of bafilomycin A1 or methylamine. Calcium content was determined using a QuantiChrom Calcium assay, ALP activity by a colorimetric assay and transcript levels by quantitative RT-PCR. Results: High phosphate increased significantly the calcium deposition, CBFA1 and ALPL mRNA expression as well as alkaline phosphatase activity in HAoSMCs, all effects ameliorated by both, bafilomycin A1 and methylamine. High phosphate further significantly up-regulated the mRNA levels of TGFB1, NFAT5 and SOX9, effects significantly blunted by additional treatment with bafilomycin A1 or methylamine. Treatment of HAoSMCs with human TGFß1 protein or high phosphate up-regulated NFAT5, SOX9, CBFA1 and ALPL mRNA expression to similarly high levels which could not be further increased by combined treatment with high phosphate and TGFß1. Bafilomycin A1 failed to reverse the osteo-/chondrogenic signaling triggered by high phosphate together with TGFß1. Conclusions: Inhibition of the vacuolar H⁺ ATPase or dissipation of the pH gradient across the membranes of acidic cellular compartments both disrupt osteo-/chondrogenic signaling and calcium deposition in VSMCs, observations supporting the hypothesis that vascular calcification requires acidic cellular compartments.

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“…An example of a personalized rare driver is PITX2, which is altered in only two patients (0.4%). PITX2 is in the TGFβ signaling pathway, which can be targeted by cancer drugs such as decanoyl-RVKR chloromethylketone in GBM [65,66].…”

Section: Discovering Personalized Driversmentioning

confidence: 99%

DawnRank: discovering personalized driver genes in cancer

Hou

2014

Genome Med

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Large-scale cancer genomic studies have revealed that the genetic heterogeneity of the same type of cancer is greater than previously thought. A key question in cancer genomics is the identification of driver genes. Although existing methods have identified many common drivers, it remains challenging to predict personalized drivers to assess rare and even patient-specific mutations. We developed a new algorithm called DawnRank to directly prioritize altered genes on a single patient level. Applications to TCGA datasets demonstrated the effectiveness of our method. We believe DawnRank complements existing driver identification methods and will help us discover personalized causal mutations that would otherwise be obscured by tumor heterogeneity. Source code can be accessed at

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Lysosomotropic drugs inhibit maturation of transforming growth factor-β

Cited by 33 publications

References 29 publications

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Inhibition of Phosphate-Induced Vascular Smooth Muscle Cell Osteo-/Chondrogenic Signaling and Calcification by Bafilomycin A1 and Methylamine

DawnRank: discovering personalized driver genes in cancer

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