A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury

Novitskaya, Tatiana; McDermott, Lee A.; Zhang, Ke Xin; Chiba, Takuto; Paueksakon, Paisit; Hukriede, Neil A.; Caestecker, Mark P. de

doi:10.1152/ajprenal.00534.2013

Cited by 72 publications

(59 citation statements)

References 51 publications

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“…39 Moreover, epigenetic alterations can be activated after kidney injury, including histone modifications, DNA methylation, and chromosomal conformational changes that regulate gene expression. There have been studies showing that histone deacetylase inhibitors accelerate recovery and decrease postinjury fibrosis after I/R 40 and aristolochic acid nephrotoxicity, 41 suggesting that epigenetic changes may influence the transition of AKI to CKD.…”

Section: Question 3 What Are the Relevant Biochemical Pathways Relatmentioning

confidence: 99%

Progression after AKI

Basile

Bonventre

Mehta

et al. 2016

Journal of the American Society of Nephrology

375

298

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Recent clinical studies indicate a strong link between AKI and progression of CKD. The increasing prevalence of AKI must compel the nephrology community to consider the long-term ramifications of this syndrome. Considerable gaps in knowledge exist regarding the connection between AKI and CKD. The 13th Acute Dialysis Quality Initiative meeting entitled "Therapeutic Targets of Human Acute Kidney Injury: Harmonizing Human and Experimental Animal Acute Kidney Injury" convened in April of 2014 and assigned a working group to focus on issues related to progression after AKI. This article provides a summary of the key conclusions and recommendations of the group, including an emphasis on terminology related to injury and repair processes for both clinical and preclinical studies, elucidation of pathophysiologic alterations of AKI, identification of potential treatment strategies, identification of patients predisposed to progression, and potential management strategies.

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Section: Question 3 What Are the Relevant Biochemical Pathways Relatmentioning

confidence: 99%

Progression after AKI

Basile

Bonventre

Mehta

et al. 2016

Journal of the American Society of Nephrology

375

298

View full text Add to dashboard Cite

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“…primers (14,41) and labeled using SYBR Green Supermix PCR (Bio-Rad, Hercules, CA). Gene expression is expressed as relative gene expression calculated using the 2 ϪddCT method, as described (54).…”

Section: Ir-aki In Micementioning

confidence: 99%

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Skrypnyk

Voziyan

Yang

et al. 2016

American Journal of Physiology-Renal Physiology

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Acute kidney injury (AKI) is a common and independent risk factor for death and chronic kidney disease (CKD). Despite promising preclinical data, there is no evidence that antioxidants reduce the severity of injury, increase recovery, or prevent CKD in patients with AKI. Pyridoxamine (PM) is a structural analog of vitamin B6 that interferes with oxidative macromolecular damage via a number of different mechanisms and is in a phase 3 clinical efficacy trial to delay CKD progression in patients with diabetic kidney disease. Because oxidative stress is implicated as one of the main drivers of renal injury after AKI, the ability of PM to interfere with multiple aspects of oxidative damage may be favorable for AKI treatment. In these studies we therefore evaluated PM treatment in a mouse model of AKI. Pretreatment with PM caused a dose-dependent reduction in acute tubular injury, long-term postinjury fibrosis, as well as improved functional recovery after ischemia-reperfusion AKI (IR-AKI). This was associated with a dose-dependent reduction in the oxidative stress marker isofuran-to-F2-isoprostane ratio, indicating that PM reduces renal oxidative damage post-AKI. PM also reduced postinjury fibrosis when administered 24 h after the initiating injury, but this was not associated with improvement in functional recovery after IR-AKI. This is the first report showing that treatment with PM reduces short- and long-term injury, fibrosis, and renal functional recovery after IR-AKI. These preclinical findings suggest that PM, which has a favorable clinical safety profile, holds therapeutic promise for AKI and, most importantly, for prevention of adverse long-term outcomes after AKI.

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“…In contrast to the necessity of the class I HDAC activity in promoting renal and liver regeneration after acute injury, there are also reports showing that HDAC inhibition accelerates renal recovery after injury in murine models of AKI induced by I/R or aristolochic acid (5,20). These effects were demonstrated by the same group using another HDAC inhibitor, methyl-4-(phenythio) butanoate (m4PTB), and mechanistically linked to acceleration of cell cycle progression and reduction of G2/M arrest of regenerating renal tubular epithelial cells and inhibition of fibrosis (5,20).…”

Section: F314mentioning

confidence: 99%

“…These effects were demonstrated by the same group using another HDAC inhibitor, methyl-4-(phenythio) butanoate (m4PTB), and mechanistically linked to acceleration of cell cycle progression and reduction of G2/M arrest of regenerating renal tubular epithelial cells and inhibition of fibrosis (5,20). Unlike MS-275, the capacity and profile of m4PTB-inactivated HDACs remain unclear.…”

Section: F314mentioning

confidence: 99%

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Class I HDAC activity is required for renal protection and regeneration after acute kidney injury

Tang

Yan

Zhao

et al. 2014

American Journal of Physiology-Renal Physiology

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Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs.

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A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury

Cited by 72 publications

References 51 publications

Progression after AKI

Progression after AKI

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Class I HDAC activity is required for renal protection and regeneration after acute kidney injury

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