HDAC inhibitors in kidney development and disease

Brilli, Lauren L.; Swanhart, Lisa M.; Caestecker, Mark P. de; Hukriede, Neil A.

doi:10.1007/s00467-012-2320-8

Cited by 54 publications

(33 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HDACis are known to have distinct effects on cell cycle checkpoint arrest, DNA instability and repair mechanisms in transformed versus primary cells. 43,44 In addition, the HDACi TSA stimulates cell proliferation at digit amputation sites in mice, 45 indicating that HDACis may have proliferative effects during tissue regeneration. Our data show that m4PTB increases expression of a large number of genes that promote cell cycle progression (Supplemental Table 1), particularly the G2/M phase of the cell cycle (Supplemental Table 2).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Enhances Recovery after AKI

Cosentino¹,

Skrypnyk²,

Brilli³

et al. 2013

Journal of the American Society of Nephrology

Self Cite

157

108

View full text Add to dashboard Cite

At present, there are no effective therapies to ameliorate injury, accelerate recovery, or prevent postinjury fibrosis after AKI. Here, we sought to identify candidate compounds that accelerate recovery after AKI by screening for small molecules that increase proliferation of renal progenitor cells in zebrafish embryos. One compound identified from this screen was the histone deacetylase inhibitor methyl-4-(phenylthio) butanoate, which we subsequently administered to zebrafish larvae and mice 24-48 hours after inducing AKI. In zebrafish, treatment with the compound increased larval survival and proliferation of renal tubular epithelial cells. In mice, treatment accelerated recovery, reduced postinjury tubular atrophy and interstitial fibrosis, and increased the regenerative capacity of actively cycling renal tubular cells by decreasing the number of cells in G2/M arrest. These data suggest that accelerating recovery may be a viable approach to treating AKI and provide proof of concept that a screen in zebrafish embryos can identify therapeutic candidates for kidney injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Enhances Recovery after AKI

Cosentino¹,

Skrypnyk²,

Brilli³

et al. 2013

Journal of the American Society of Nephrology

Self Cite

157

108

View full text Add to dashboard Cite

show abstract

“…Several small molecule inhibitors of SIRTs were reported recently, such as splitomicin and its derivatives, sirtinol, AGK2, cambinol, suramin and tenovin [24]. Class I and II HDACs inhibitors exert anti-inflammatory and anti-fibrotic effects in kidney diseases [32]. Inhibition of the SIRT2 pathway is also anti-fibrotic.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

You

Wang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD⁺-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. Methods: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, α-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. Results: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-β1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-β1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-β1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-β1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-β1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. Conclusion: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis.

show abstract

“…HDAC inhibition exerts anti-fibrotic and anti-inflammation functions in numerous animal models of kidney diseases [37,38]; however, the particular HDAC isotypes involved in different disease models or cell types are not fully revealed. Recent studies showed that HDAC2 [39] was upregulated by TGF-β in diabetic kidney and HDAC4 [40] was involved in STZ-induced diabetic rat model, indicating that one or several HDAC members might be actively involved in a specific disease setting.…”

Section: Discussionmentioning

confidence: 99%

TGF-β induces miR-30d down-regulation and podocyte injury through Smad2/3 and HDAC3-associated transcriptional repression

et al. 2015

View full text Add to dashboard Cite

The microRNA-30 family plays important roles in maintaining kidney homeostasis. Patients with focal segmental glomerulosclerosis (FSGS) have reduced miR-30 levels in glomerulus. TGF-β represses miR-30s in kidney podocytes, which leads to cytoskeleton damage and podocyte apoptosis. In this study, we investigated the mechanism by which TGF-β represses miR-30d in vitro. The human miR-30d promoter contains multiple copies of Smad binding element-like sequences. A fragment of 150 base pairs close to the transcription start site was negatively regulated by TGF-β to a similar extent as the 1.8 kb promoter, which was blocked by histone-deacetylase inhibition. TGF-β specifically enhanced HDAC3 expression. Knockdown of HDAC3 by shRNA or a selective inhibitor RGFP966 significantly relieved the repression of miR-30d mRNA and the promoter transcription. TGF-β promoted HDAC3 association with Smad2/3 and NCoR and caused their accumulation at the putative Smad binding site on the miR-30d promoter, which was prohibited by TSA or RGFP966. Furthermore, TSA or RGFP966 treatment reversed TGF-β-induced up-regulation of miR-30d targets Notch1 and p53 and alleviated the podocyte cytoskeleton damage and apoptosis. Taken together, these findings pinpoint that TGF-β represses miR-30d through a Smad2/3-HDAC3-NCoR repression complex and provide novel insights into a potential target for the treatment of podocyte injury-associated glomerulopathies. Key message: MiR-30d promoter is negatively regulated by TGF-β. TGF-β down-regulates miR-30 through Smad signaling pathway. HDAC3 and NCoR are recruited by Smad2/3 to mediate miR-30d repression by TGF-β. HDAC3 acts as a critical player in TGF-β-induced miR-30d repression and podocyte injuries.

show abstract

HDAC inhibitors in kidney development and disease

Cited by 54 publications

References 112 publications

Histone Deacetylase Inhibitor Enhances Recovery after AKI

Histone Deacetylase Inhibitor Enhances Recovery after AKI

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

TGF-β induces miR-30d down-regulation and podocyte injury through Smad2/3 and HDAC3-associated transcriptional repression

Contact Info

Product

Resources

About