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Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice

View Article: PubMed Central - PubMed

ABSTRACT

Bone loss and increased fracture are the devastating outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD) resulting from Klotho deficit-related mineral disturbance and hyperparathyroidism. Because Klotho down-regulation after renal injury is presumably affected by aberrant histone deacetylase (HDAC) activities, here we assess whether HDAC inhibition prevents Klotho loss and attenuates the CKD-associated bone complication in a mouse model of CKD-MBD. Mice fed adenine-containing diet developed the expected renal damage, a substantial Klotho loss and the deregulated key factors causally affecting bone remodeling, which were accompanied by a marked reduction of bone mineral density. Intriguingly, administration of a potent HDAC inhibitor trichostatin A (TSA) impressively alleviated the Klotho deficit and the observed alterations of serum, kidney and bone. TSA prevented Klotho loss by increasing the promoter-associated histone acetylation, therefore increasing Klotho transcription. More importantly the mice lacking Klotho by siRNA interference largely abolished the TSA protections against the serum and renal abnormalities, and the deranged bone micro-architectures. Thus, our study identified Klotho loss as a key event linking HDAC deregulation to the renal and bone injuries in CKD-MBD mice and demonstrated the therapeutic potentials of endogenous Klotho restoration by HDAC inhibition in treating CKD and the associated extrarenal complications.

No MeSH data available.


Related in: MedlinePlus

HDAC inhibition attenuates CKD-associated abnormalities of mineral, hormone and bone remodeling-related gene expression.(A) Average concentrations of serum phosphorus (P), intact parathyroid hormone (iPTH), FGF23 and 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3 from Control, TSA, adenine and TSA-treated adenine mice of 6 weeks (n = 6). (B) Renal BMP-7 and phosphorylated Smad3 (P-Smad3) were examined from all mice by Western blotting (two randomly selected samples from each group were shown). Beta-actin (β-actin) served as loading control. (C) Quantifications of Figure 2B (n = 6 in each group). (D) Average levels of bone Runx2 and Spp1 mRNA examined by qRT-PCT (n = 6). The data are presented as mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05 versus adenine mice.
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f2: HDAC inhibition attenuates CKD-associated abnormalities of mineral, hormone and bone remodeling-related gene expression.(A) Average concentrations of serum phosphorus (P), intact parathyroid hormone (iPTH), FGF23 and 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3 from Control, TSA, adenine and TSA-treated adenine mice of 6 weeks (n = 6). (B) Renal BMP-7 and phosphorylated Smad3 (P-Smad3) were examined from all mice by Western blotting (two randomly selected samples from each group were shown). Beta-actin (β-actin) served as loading control. (C) Quantifications of Figure 2B (n = 6 in each group). (D) Average levels of bone Runx2 and Spp1 mRNA examined by qRT-PCT (n = 6). The data are presented as mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05 versus adenine mice.

Mentions: To gain further insight into the molecular basis of TSA protection of CKD-associated bone injury, we examined a number of key factors and osteogenic markers closely related to bone remodeling. Adenine mice displayed elevated serum phosphate, intact parathyroid hormone (iPTH) and FGF23, and decreased 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3) (Fig. 2A) - the characteristic serological changes of CKD-MBD that causally related to bone damage. Bone morphogenesis protein-7 (BMP-7) is a kidney-enriched protein released into circulation and beneficially regulates renal function and bone remodeling, which is significantly reduced; while the phosphorylated Smad3, the active form of Smad3 mediating transforming growth factor-beta (TGFβ) signaling leading to myofibroblast trans-differentiation and extra cellular matrix protein expression, is dramatically induced in adenine mouse kidney (Fig. 2B,C). In addition, the femurs of adenine mice expressed reduced Runx2 (runt-related transcription factor 2) - a transcription factor critical for osteoblast differentiation and Spp1 (Secreted phosphoprotein 1) - an extracellular matrix protein essential for bone mass maintenance (Fig. 2D). Intriguingly TSA treatment significantly mitigated all these abnormalities, indicating that HDAC inhibition improves renal function and beneficially affects the CKD-associated bone remodeling.


Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice
HDAC inhibition attenuates CKD-associated abnormalities of mineral, hormone and bone remodeling-related gene expression.(A) Average concentrations of serum phosphorus (P), intact parathyroid hormone (iPTH), FGF23 and 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3 from Control, TSA, adenine and TSA-treated adenine mice of 6 weeks (n = 6). (B) Renal BMP-7 and phosphorylated Smad3 (P-Smad3) were examined from all mice by Western blotting (two randomly selected samples from each group were shown). Beta-actin (β-actin) served as loading control. (C) Quantifications of Figure 2B (n = 6 in each group). (D) Average levels of bone Runx2 and Spp1 mRNA examined by qRT-PCT (n = 6). The data are presented as mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05 versus adenine mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5384196&req=5

f2: HDAC inhibition attenuates CKD-associated abnormalities of mineral, hormone and bone remodeling-related gene expression.(A) Average concentrations of serum phosphorus (P), intact parathyroid hormone (iPTH), FGF23 and 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3 from Control, TSA, adenine and TSA-treated adenine mice of 6 weeks (n = 6). (B) Renal BMP-7 and phosphorylated Smad3 (P-Smad3) were examined from all mice by Western blotting (two randomly selected samples from each group were shown). Beta-actin (β-actin) served as loading control. (C) Quantifications of Figure 2B (n = 6 in each group). (D) Average levels of bone Runx2 and Spp1 mRNA examined by qRT-PCT (n = 6). The data are presented as mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05 versus adenine mice.
Mentions: To gain further insight into the molecular basis of TSA protection of CKD-associated bone injury, we examined a number of key factors and osteogenic markers closely related to bone remodeling. Adenine mice displayed elevated serum phosphate, intact parathyroid hormone (iPTH) and FGF23, and decreased 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3) (Fig. 2A) - the characteristic serological changes of CKD-MBD that causally related to bone damage. Bone morphogenesis protein-7 (BMP-7) is a kidney-enriched protein released into circulation and beneficially regulates renal function and bone remodeling, which is significantly reduced; while the phosphorylated Smad3, the active form of Smad3 mediating transforming growth factor-beta (TGFβ) signaling leading to myofibroblast trans-differentiation and extra cellular matrix protein expression, is dramatically induced in adenine mouse kidney (Fig. 2B,C). In addition, the femurs of adenine mice expressed reduced Runx2 (runt-related transcription factor 2) - a transcription factor critical for osteoblast differentiation and Spp1 (Secreted phosphoprotein 1) - an extracellular matrix protein essential for bone mass maintenance (Fig. 2D). Intriguingly TSA treatment significantly mitigated all these abnormalities, indicating that HDAC inhibition improves renal function and beneficially affects the CKD-associated bone remodeling.

View Article: PubMed Central - PubMed

ABSTRACT

Bone loss and increased fracture are the devastating outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD) resulting from Klotho deficit-related mineral disturbance and hyperparathyroidism. Because Klotho down-regulation after renal injury is presumably affected by aberrant histone deacetylase (HDAC) activities, here we assess whether HDAC inhibition prevents Klotho loss and attenuates the CKD-associated bone complication in a mouse model of CKD-MBD. Mice fed adenine-containing diet developed the expected renal damage, a substantial Klotho loss and the deregulated key factors causally affecting bone remodeling, which were accompanied by a marked reduction of bone mineral density. Intriguingly, administration of a potent HDAC inhibitor trichostatin A (TSA) impressively alleviated the Klotho deficit and the observed alterations of serum, kidney and bone. TSA prevented Klotho loss by increasing the promoter-associated histone acetylation, therefore increasing Klotho transcription. More importantly the mice lacking Klotho by siRNA interference largely abolished the TSA protections against the serum and renal abnormalities, and the deranged bone micro-architectures. Thus, our study identified Klotho loss as a key event linking HDAC deregulation to the renal and bone injuries in CKD-MBD mice and demonstrated the therapeutic potentials of endogenous Klotho restoration by HDAC inhibition in treating CKD and the associated extrarenal complications.

No MeSH data available.


Related in: MedlinePlus