Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Inoue, Kazunori; Gan, Geliang; Ciarleglio, Maria; Zhang, Yan; Tian, Xuefei; Pedigo, Christopher E.; Cavanaugh, Corey; Tate, Janet P.; Wang, Ying; Cross, Elizabeth; Groener, Marwin; Chai, Nathan; Wang, Zhen; Justice, Amy C.; Zhang, Zhenhai; Parikh, Chirag R.; Wilson, F. Perry; Ishibe, Shuta

doi:10.1172/jci124030

Cited by 47 publications

(46 citation statements)

References 80 publications

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“…The low P‐gp and high HDAC2 expression and function may be an association seen with steroid responsiveness and further mechanistic studies are required to demonstrate causation. Nevertheless, the findings are significant and make an interesting case for modulation of HDAC2 or P‐gp expression and function across a broad variety of inflammatory and autoimmune diseases …”

mentioning

confidence: 99%

Retracted: When doing the right thing is wrong: Drug efflux pumps in steroid‐resistant nephrotic syndrome

Chowdhary

2020

Int J of Rheum Dis

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mentioning

confidence: 99%

Retracted: When doing the right thing is wrong: Drug efflux pumps in steroid‐resistant nephrotic syndrome

Chowdhary

2020

Int J of Rheum Dis

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“…We further demonstrated that podocyte injury is associated with suppression of autophagy and exacerbation of inflammation by HDAC4mediated signal transducers and activators of transcription factor 1 (STAT1) signaling [17]. A very recent study also confirmed that podocyte HDAC activity regulates murine and human glomerular diseases [18]. It is found that HDAC1 and HDAC2 activities are increased in mice podocytopathy models and podocyte-associated HDAC1 and HDAC2 genetic ablation improves proteinuria and glomerulosclerosis through regulation of early growth response 1 (EGR1) [18].…”

Section: Zn 2+ -Dependent Hdac On Regulation Of Podocyte Functionmentioning

confidence: 71%

“…A very recent study also confirmed that podocyte HDAC activity regulates murine and human glomerular diseases [18]. It is found that HDAC1 and HDAC2 activities are increased in mice podocytopathy models and podocyte-associated HDAC1 and HDAC2 genetic ablation improves proteinuria and glomerulosclerosis through regulation of early growth response 1 (EGR1) [18]. Furthermore, when studying the toxic effects of prenatal caffeine exposure (PCE) on podocyte development in male offspring, Zhu et al [19] found that HDAC7 can reduce Krüppel-like factor 4 (KLF4) expression via downregulation of the H3K9ac level in the KLF4 promoter, resulting in podocyte developmental toxicity induced by PCE in male offspring rats.…”

Section: Zn 2+ -Dependent Hdac On Regulation Of Podocyte Functionmentioning

confidence: 72%

“…These data indicate that VPA treatment in an early phase of renal disease can halt and even prevent the development of proteinuria and the progression of kidney damage. In another animal model, VPA or SAHA was demonstrated to mitigate foot process effacement of podocyte and proteinuria in Tln1 fl/fl Pod-rtTA TetO-Cre mice, which constitutes an adult genetic mouse model for proteinuric kidney disease by ablating Tln1 in podocytes in a conditional doxycycline-inducible manner [18]. Very excitedly, VPA was demonstrated to reduce the mean annual decrease in the estimated glomerular filtration rate in proteinuric patients from a longitudinal analysis of the multicenter Veterans Aging Cohort Study [18].…”

Section: Therapeutic Effects Of Zn 2+ -Dependent Hdac Inhibitors In Pmentioning

confidence: 99%

“…In another animal model, VPA or SAHA was demonstrated to mitigate foot process effacement of podocyte and proteinuria in Tln1 fl/fl Pod-rtTA TetO-Cre mice, which constitutes an adult genetic mouse model for proteinuric kidney disease by ablating Tln1 in podocytes in a conditional doxycycline-inducible manner [18]. Very excitedly, VPA was demonstrated to reduce the mean annual decrease in the estimated glomerular filtration rate in proteinuric patients from a longitudinal analysis of the multicenter Veterans Aging Cohort Study [18]. Furthermore, it has been found that VPA ameliorates podocyte and renal injuries mainly by facilitating the autophagy and inactivation of NF-κB/inducible nitric oxide synthase (iNOS) signaling in DN [23].…”

Section: Therapeutic Effects Of Zn 2+ -Dependent Hdac Inhibitors In Pmentioning

confidence: 99%

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Histone Deacetylases Take Center Stage on Regulation of Podocyte Function

et al. 2020

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Background: Podocytes (highly specialized and terminally differentiated epithelial cells) are integral components of the glomerular filtration barrier that are vulnerable to a variety of injuries and, as a result, they undergo a series of changes ranging from hypertrophy to detachment and apoptosis. Podocyte injury is a major determinant in proteinuric kidney disease and identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Although numerous studies have achieved dramatic advances in the understanding of podocyte biology and its relevance to renal injury, few effective and specific therapies are available. Summary: Epigenetic modifications have been proven to play important roles in the pathogenesis of kidney diseases. Among them, histone deacetylase (HDAC)-mediated epigenetic acetylation in the kidney has attracted much attention, which may play multiple roles in both kidney development and the pathogenesis of kidney disease. Recent studies have demonstrated that HDAC protect against podocyte injury by regulation of inflammation, apoptosis, autophagy, mitochondrial function, and insulin resistance. In this review, we summarize recent advances in the understanding of the functions and regulatory mechanisms of HDAC in podocytes and associated proteinuric kidney diseases. In addition, we provide evidence of the potential therapeutic effects of HDAC inhibitors for proteinuric kidney disease. Key Messages: Pharmacological targeting of HDAC-mediated epigenetic processes may open new therapeutic avenues for chronic kidney disease.

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Hdac1 and Hdac2 positively regulate Notch1 gain‐of‐function pathogenic signaling in committed osteoblasts of male mice

Torres,

Hinojosa,

VanCleave

et al. 2023

Birth Defects Research

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BackgroundSkeletal development requires precise extrinsic and intrinsic signals to regulate processes that form and maintain bone and cartilage. Notch1 is a highly conserved signaling receptor that regulates cell fate decisions by controlling the duration of transcriptional bursts. Epigenetic molecular events reversibly modify DNA and histone tails by influencing the spatial organization of chromatin and can fine‐tune the outcome of a Notch1 transcriptional response. Histone deacetylase 1 and 2 (HDAC1 and HDAC2) are chromatin modifying enzymes that mediate osteoblast differentiation. While an HDAC1‐Notch interaction has been studied in vitro and in Drosophila, its role in mammalian skeletal development and disorders is unclear. Osteosclerosis is a bone disorder with an abnormal increase in the number of osteoblasts and excessive bone formation.MethodsHere, we tested whether Hdac1/2 contribute to the pathogenesis of osteosclerosis in a murine model of the disease owing to conditionally cre‐activated expression of the Notch1 intracellular domain in immature osteoblasts.ResultsImportantly, selective homozygous deletions of Hdac1/2 in osteoblasts partially alleviate osteosclerotic phenotypes (Col2.3kb‐Cre; TGRosaN1ICD/+; Hdac1flox/flox; Hdac2flox/flox) with a 40% decrease in bone volume and a 22% decrease in trabecular thickness in 4 weeks old when compared to male mice with heterozygous deletions of Hdac1/2 (Col2.3 kb‐Cre; TGRosaN1ICD/+; Hdac1flox/+; Hdac2flox/+). Osteoblast‐specific deletion of Hdac1/2 in male and female mice results in no overt bone phenotype in the absence of the Notch1 gain‐of‐function (GOF) allele.ConclusionsThese results provide evidence that Hdac1/2 contribute to Notch1 pathogenic signaling in the mammalian skeleton. Our study on epigenetic regulation of Notch1 GOF‐induced osteosclerosis may facilitate further mechanistic studies of skeletal birth defects caused by Notch‐related GOF mutations in human patients, such as Adams‐Oliver disease, congenital heart disease, and lateral meningocele syndrome.

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Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Cited by 47 publications

References 80 publications

Retracted: When doing the right thing is wrong: Drug efflux pumps in steroid‐resistant nephrotic syndrome

Retracted: When doing the right thing is wrong: Drug efflux pumps in steroid‐resistant nephrotic syndrome

Histone Deacetylases Take Center Stage on Regulation of Podocyte Function

Hdac1 and Hdac2 positively regulate Notch1 gain‐of‐function pathogenic signaling in committed osteoblasts of male mice

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