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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.


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HDAC inhibition prevents CKD-associated renal and bone damage in adenine-fed mice.(A) Representative Masson’s trichrome staining of kidney sections and H&E stained femur sections from control, TSA, adenine and TSA-treated adenine mice (n = 6 in each group, 6 weeks). (B) Semi-quantifications of renal interstitial fibrosis (the percentage of blue-colored cortex area over the whole cortex field from Masson’s trichrome-stained sections) from all mice. (C) Average levels of serum blood urea nitrogen (BUN) and Creatinine (Cre). The quantifications were based on all mice tested. (D) Representative femur radiographs from Control, TSA, adenine and TSA-treated adenine mice. The lower panels are the enlarged views of framed images above (E) Quantifications of bone density of Fig. 1D from all mice. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05, ##P < 0.01 versus adenine mice.
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f1: HDAC inhibition prevents CKD-associated renal and bone damage in adenine-fed mice.(A) Representative Masson’s trichrome staining of kidney sections and H&E stained femur sections from control, TSA, adenine and TSA-treated adenine mice (n = 6 in each group, 6 weeks). (B) Semi-quantifications of renal interstitial fibrosis (the percentage of blue-colored cortex area over the whole cortex field from Masson’s trichrome-stained sections) from all mice. (C) Average levels of serum blood urea nitrogen (BUN) and Creatinine (Cre). The quantifications were based on all mice tested. (D) Representative femur radiographs from Control, TSA, adenine and TSA-treated adenine mice. The lower panels are the enlarged views of framed images above (E) Quantifications of bone density of Fig. 1D from all mice. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05, ##P < 0.01 versus adenine mice.

Mentions: To gain insights into the therapeutic efficacy of HDAC inhibition on CKD-associated bone complication, we established an adenine-fed mouse model of CKD-MBD323334. We divided mice into control, TSA, adenine, and TSA-treated adenine groups and found that the kidneys from adenine mice fed 6 weeks developed extensive renal pathological changes such as renal tubular atrophy and interstitial fibrosis (Fig. 1A upper panel and Fig. 1B). In addition, adenine mice had marked increases of blood urine nitrogen (BUN) and creatinine (Fig. 1C) - two major parameters indicating the low glomerular infiltration rate due to renal functional loss. The histological examination of adenine mice revealed the marked osteoporosis-like changes on distal femurs - the thinner and deranged trabeculae with increased lacuna (Fig. 1A, the white arrow heads in lower panel). The X-ray scanning showed the marked loss of bone mineral density (BMD) at the distal femurs (Fig. 1D,E). Impressively, TSA (trichostatin A), a potent general HDAC inhibitor frequently used in HDAC inhibition study, effectively reduced the renal tubule damage and fibrosis lesions, attenuated the increased BUN and creatinine, and significantly improved the bone pathological changes and BMD loss (Fig. 1A–E). These results clearly demonstrate that HDAC inhibition protects against the renal and bone injuries in adenine mice.


Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice
HDAC inhibition prevents CKD-associated renal and bone damage in adenine-fed mice.(A) Representative Masson’s trichrome staining of kidney sections and H&E stained femur sections from control, TSA, adenine and TSA-treated adenine mice (n = 6 in each group, 6 weeks). (B) Semi-quantifications of renal interstitial fibrosis (the percentage of blue-colored cortex area over the whole cortex field from Masson’s trichrome-stained sections) from all mice. (C) Average levels of serum blood urea nitrogen (BUN) and Creatinine (Cre). The quantifications were based on all mice tested. (D) Representative femur radiographs from Control, TSA, adenine and TSA-treated adenine mice. The lower panels are the enlarged views of framed images above (E) Quantifications of bone density of Fig. 1D from all mice. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05, ##P < 0.01 versus adenine mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5384196&req=5

f1: HDAC inhibition prevents CKD-associated renal and bone damage in adenine-fed mice.(A) Representative Masson’s trichrome staining of kidney sections and H&E stained femur sections from control, TSA, adenine and TSA-treated adenine mice (n = 6 in each group, 6 weeks). (B) Semi-quantifications of renal interstitial fibrosis (the percentage of blue-colored cortex area over the whole cortex field from Masson’s trichrome-stained sections) from all mice. (C) Average levels of serum blood urea nitrogen (BUN) and Creatinine (Cre). The quantifications were based on all mice tested. (D) Representative femur radiographs from Control, TSA, adenine and TSA-treated adenine mice. The lower panels are the enlarged views of framed images above (E) Quantifications of bone density of Fig. 1D from all mice. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01 versus control; #P < 0.05, ##P < 0.01 versus adenine mice.
Mentions: To gain insights into the therapeutic efficacy of HDAC inhibition on CKD-associated bone complication, we established an adenine-fed mouse model of CKD-MBD323334. We divided mice into control, TSA, adenine, and TSA-treated adenine groups and found that the kidneys from adenine mice fed 6 weeks developed extensive renal pathological changes such as renal tubular atrophy and interstitial fibrosis (Fig. 1A upper panel and Fig. 1B). In addition, adenine mice had marked increases of blood urine nitrogen (BUN) and creatinine (Fig. 1C) - two major parameters indicating the low glomerular infiltration rate due to renal functional loss. The histological examination of adenine mice revealed the marked osteoporosis-like changes on distal femurs - the thinner and deranged trabeculae with increased lacuna (Fig. 1A, the white arrow heads in lower panel). The X-ray scanning showed the marked loss of bone mineral density (BMD) at the distal femurs (Fig. 1D,E). Impressively, TSA (trichostatin A), a potent general HDAC inhibitor frequently used in HDAC inhibition study, effectively reduced the renal tubule damage and fibrosis lesions, attenuated the increased BUN and creatinine, and significantly improved the bone pathological changes and BMD loss (Fig. 1A–E). These results clearly demonstrate that HDAC inhibition protects against the renal and bone injuries in adenine 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