Aldosterone induces renal fibrosis by promoting HDAC1 expression, deacetylating H3K9 and inhibiting klotho transcription

Lai,Lingyun; Cheng,Ping; Yan,Minhua; Gu,Yong; Xue,Jun

doi:10.3892/mmr.2018.9781

Aldosterone induces renal fibrosis by promoting HDAC1 expression, deacetylating H3K9 and inhibiting klotho transcription

Authors:
- Lingyun Lai
- Ping Cheng
- Minhua Yan
- Yong Gu
- Jun Xue
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Affiliations: Department of Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: December 20, 2018 https://doi.org/10.3892/mmr.2018.9781
Pages: 1803-1808

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Abstract

Aldosterone has an important role in the progression of renal fibrosis. In the present study, the concentration of aldosterone and klotho (KL) in the serum of patients with chronic kidney disease (CKD) were analyzed. A negative correlation was observed between aldosterone and KL, suggesting that KL may serve a protective role in CKD. Subsequently, an aldosterone‑induced CKD mouse model was established using a single nephrectomy and subcutaneous osmotic pump with aldosterone and 1% high‑salt drinking water. It was demonstrated that fibronectin 1 (Fn1) expression levels were higher in high aldosterone mice, whereas KL expression levels were low. In addition, the results demonstrated that histone deacetylase 1 (HDAC1) protein expression levels were upregulated in the renal distal convoluted tubules of high aldosterone mice, whereas acetylated H3K9 (H3K9Ac) was significantly downregulated. To determine the transcriptional activation status, chromatin immunoprecipitation polymerase chain reaction (PCR) was used to validate binding of H3K9Ac to the KL gene promoter site. It was revealed that the binding product of the KL promoter could be PCR‑amplified at the H3K9Ac site from wild‑type and low aldosterone mice; however, amplification of the binding product was not observed in high aldosterone mice. In conclusion, aldosterone significantly inhibited H3K9 acetylation by upregulating HDAC1 protein expression levels in the renal distal convoluted tubule cells, resulting in its inability to bind to the KL promoter, loss of transcription of the KL gene and increased expression of the renal fibrosis gene, Fn1.

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