Histone Deacetylase Inhibitor Enhances Recovery after AKI

Cosentino, Chiara; Skrypnyk, Nataliya I.; Brilli, Lauren L.; Chiba, Takuto; Novitskaya, Tatiana; Woods, Clara; West, James; Korotchenko, Vasiliy; McDermott, Lee A.; Day, Billy W.; Davidson, Alan J.; Harris, Raymond C.; Caestecker, Mark P. de; Hukriede, Neil A.

doi:10.1681/asn.2012111055

Cited by 159 publications

(113 citation statements)

References 53 publications

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“…For example, intervention aimed at G2/M arrested cells in proximal tubules might be considered the novel therapeutic strategies. Indeed, histone deacetylase inhibitors or p53 inhibitors have been shown to ameliorate fibrosis by decreasing G2/M arrested cells in animal models [24,26]. Translation of these strategies to humans will help the prevention of AKI-to-CKD continuum.…”

Section: Resultsmentioning

confidence: 99%

Insights into the Mechanisms of the Acute Kidney Injury-to-Chronic Kidney Disease Continuum

Takaori

Yanagita²

2016

Nephron

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Acute kidney injury (AKI) is an increasingly common clinical problem with significant impact on long-term patient outcome. Recent clinical trials demonstrate that AKI is closely related to the progression of chronic kidney disease (CKD) and end-stage renal disease, though the precise mechanisms linking AKI to CKD remain unclear. While inflammation, microvascular rarefaction and hypoxia are involved in the AKI-to-CKD continuum, proximal tubule injury seems to play an important role in the progression of CKD. In this review, we focus on the mechanisms of the AKI-to-CKD continuum, especially the mechanism by which injury to the proximal tubules triggers progression to CKD. Elucidating the mechanisms involved in the AKI-to-CKD continuum will support the development of therapeutic options to prevent progression from AKI to CKD.

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Section: Resultsmentioning

confidence: 99%

Insights into the Mechanisms of the Acute Kidney Injury-to-Chronic Kidney Disease Continuum

Takaori

Yanagita²

2016

Nephron

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“…This mesenchymal populace proliferates and migrates to occupy the denuded basement membrane where damage has occurred. Interestingly, in both mammals and zebrafish, the mesenchymal populace that regenerates nephrons after AKI expresses Pax2 (Imgrund, et al, 1999; Cosentino, et al, 2013). Thus, it is intriguing to speculate whether the absence of polarity in the pronephros of prkcι/ζ morphants, and the consequent expression of developmental factors, capitulates aspects of tubular injury.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish pronephros tubulogenesis and epithelial identity maintenance are reliant on the polarity proteins Prkc iota and zeta

Gerlach

Wingert

2014

Developmental Biology

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The zebrafish pronephros provides an excellent in vivo system to study the mechanisms of vertebrate nephron development. When and how renal progenitors in the zebrafish embryo undergo tubulogenesis to form nephrons is poorly understood, but is known to involve a mesenchymal to epithelial transition (MET) and the acquisition of polarity. Here, we determined the precise timing of these events in pronephros tubulogenesis. As the ternary polarity complex is an essential regulator of epithelial cell polarity across tissues, we performed gene knockdown studies to assess the roles of the related factors atypical protein kinase C iota and zeta (prkcι, prkcζ). We found that prkcι and prkcζ serve partially redundant functions to establish pronephros tubule epithelium polarity. Further, the loss of prkcι or the combined knockdown of prkcι/ζ disrupted proximal tubule morphogenesis and podocyte migration due to cardiac defects that prevented normal fluid flow to the kidney. Surprisingly, tubule cells in prkcι/ζ morphants displayed ectopic expression of the transcription factor pax2a and the podocyte-associated genes wt1a, wt1b, and podxl, suggesting that prkcι/ζ are needed to maintain renal epithelial identity. Knockdown of genes essential for cardiac contractility and vascular flow to the kidney, such as tnnt2a, or elimination of pronephros fluid output through knockdown of the intraflagellar transport gene ift88, was not associated with ectopic pronephros gene expression, thus suggesting a unique role for prkcι/ζ in maintaining tubule epithelial identity separate from the consequence of disruptions to renal fluid flow. Interestingly, knockdown of pax2a, but not wt1a, was sufficient to rescue ectopic tubule gene expression in prkcι/ζ morphants. These data suggest a model in which the redundant activities of prkcι and prkcζ are essential to establish tubule epithelial polarity and also serve to maintain proper epithelial cell type identity in the tubule by inhibiting pax2a expression. These studies provide a valuable foundation for further analysis of MET during nephrogenesis, and have implications for understanding the pathways that affect nephron epithelial cells during kidney disease and regeneration.

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“…To date, however, several exciting lines of evidence support the notion that renal regeneration research using zebrafish can indeed provide relevant comparative insights into human AKI that may also have direct translational potential 56–58 . Chemical screening to identify small molecules that increase the proliferation of renal progenitor cells in the zebrafish embryo recently led to the identification of the histone deacetylase inhibitor methyl-4-(phenylthio)-butanoate (m4PTB) 56,57 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of Nephron Composition and Function in the Adult Zebrafish Kidney

McCampbell

Springer

Wingert

2014

JoVE

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The zebrafish model has emerged as a relevant system to study kidney development, regeneration and disease. Both the embryonic and adult zebrafish kidneys are composed of functional units known as nephrons, which are highly conserved with other vertebrates, including mammals. Research in zebrafish has recently demonstrated that two distinctive phenomena transpire after adult nephrons incur damage: first, there is robust regeneration within existing nephrons that replaces the destroyed tubule epithelial cells; second, entirely new nephrons are produced from renal progenitors in a process known as neonephrogenesis. In contrast, humans and other mammals seem to have only a limited ability for nephron epithelial regeneration. To date, the mechanisms responsible for these kidney regeneration phenomena remain poorly understood. Since adult zebrafish kidneys undergo both nephron epithelial regeneration and neonephrogenesis, they provide an outstanding experimental paradigm to study these events. Further, there is a wide range of genetic and pharmacological tools available in the zebrafish model that can be used to delineate the cellular and molecular mechanisms that regulate renal regeneration. One essential aspect of such research is the evaluation of nephron structure and function. This protocol describes a set of labeling techniques that can be used to gauge renal composition and test nephron functionality in the adult zebrafish kidney. Thus, these methods are widely applicable to the future phenotypic characterization of adult zebrafish kidney injury paradigms, which include but are not limited to, nephrotoxicant exposure regimes or genetic methods of targeted cell death such as the nitroreductase mediated cell ablation technique. Further, these methods could be used to study genetic perturbations in adult kidney formation and could also be applied to assess renal status during chronic disease modeling.

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Histone Deacetylase Inhibitor Enhances Recovery after AKI

Cited by 159 publications

References 53 publications

Insights into the Mechanisms of the Acute Kidney Injury-to-Chronic Kidney Disease Continuum

Insights into the Mechanisms of the Acute Kidney Injury-to-Chronic Kidney Disease Continuum

Zebrafish pronephros tubulogenesis and epithelial identity maintenance are reliant on the polarity proteins Prkc iota and zeta

Analysis of Nephron Composition and Function in the Adult Zebrafish Kidney

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