Dataset Information

Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy.

ABSTRACT: Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment.

SUBMITTER: Liu F

PROVIDER: S-EPMC5025656 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy.

Liu Feng F Zong Ming M Wen Xiaofei X Li Xuezhu X Wang Jun J Wang Yi Y Jiang Wei W Li Xiaojun X Guo Zhongliang Z Qi Hualin H

Scientific reports 20160916

Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly ...[more]

PMID: 27633396

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Project description:Diabetic nephropathy (DN) is a common complication in patients with diabetes and a leading cause of mortality. The management of DN in the clinic still remains a challenge. Therefore, the identification of novel compounds for DN treatment and their characterization in preclinical DN models are crucial. Isoeucommin A is a lignan compound isolated from Eucommia ulmoides Oliv, which has not been studied in detail. Our aim was to investigate the effect of Isoeucommin A in DN and to elucidate the molecular mechanisms though which Isoeucommin A acts in vitro and in vivo. We first isolated and purified Isoeucommin A by microporous resin column chromatography and studied the mass spectrogram, as well as the structure of Isoeucommin A, by high-resolution electrospray ionization mass spectroscopy and NMR, respectively. We further established an in vivo rat DN model and measured the changes of blood glucose, body weight, kidney index (KI), blood urea nitrogen, creatinine (CRE), glutathione, malondialdehyde (MDA), SOD, albumin (ALB) and urinary ALB to CRE ratios on treatment with Isoeucommin A. In addition, we measured SOD, MDA, glycogen synthase kinase-3β (GSK-3β), phosphorylated (p)-GSK-3β, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels by quantitative real-time PCR and western blot, and estimated cell viability by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. After Isoeucommin A treatment, body weight, as well as SOD, glutathione, HO-1 and Nrf2 expression levels, in DN rats increased in a dose-dependent manner. In contrast, the levels of blood glucose, KI, blood urea nitrogen, CRE, urinary ALB to CRE ratio, tumor necrosis factor-α, interleukin-1β, interleukin-6 and MDA decreased significantly. In addition, Isoeucommin A protected H2 O2 -stimulated renal tubular epithelial cells from oxidative stress and activated the Nrf2/HO-1 signaling pathway in high-glucose-stimulated human renal mesangial cells. In conclusion, Isoeucommin A could alleviate inflammation and oxidative stress in in vitro and in vivo DN models and thus attenuate kidney injury by activating the Nrf2/HO-1 signaling pathway. Isoeucommin A could have the potential to be used as an effective drug for the treatment of DN.

Dataset Information

Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy.

Publications

Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy.

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