Epigenetic regulation in the acute kidney injury to chronic kidney disease transition

Rodríguez-Romo, Roxana; Berman, Nathan; Gómez, Armando Torres; Bobadilla, Norma A

doi:10.1111/nep.12521

Cited by 45 publications

(38 citation statements)

References 63 publications

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“…Epigenetic mechanisms, including histone acetylation, have been reported to be involved in the progression from acute kidney injury to chronic kidney diseases [24]. The histone acetylation state is regulated by the activity of histone acetylases and deacetylases, which have been implicated as key regulators of diabetes- and TGF-β1-induced renal fibrosis [25], [26].…”

Section: Discussionmentioning

confidence: 99%

Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression

Zhou

Gong

et al. 2017

Redox Biology

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Uncovering new therapeutic targets for renal fibrosis holds promise for the treatment of chronic kidney diseases. Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively ameliorate pathological fibrotic responses. However, the pharmacological effects and underlying mechanisms of these inhibitors in renal fibrosis remain elusive. In this study, we determined that the inhibition of Brd4, a BET family member, with a selective potent chemical inhibitor, JQ1, could prevent the development of renal fibrosis and block the progression of fibrosis in rats that have undergone unilateral ureteral obstruction (UUO). Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in decreased expression of fibrotic genes such as α-smooth muscle actin, collagen IV and fibronectin both in UUO-induced fibrosis and upon TGF-β1 stimulation in HK-2 cells. Brd4 inhibition also suppressed the oxidative stress induced by UUO in vivo or by TGF-β1 in HK-2 cells. Moreover, Nox4, which is constitutively active in renal cells and is involved in the generation of hydrogen peroxide, was up-regulated during UUO-mediated fibrosis and induced by TGF-β1 in HK-2 cells, and this up-regulation could be blunted by Brd4 inhibition. Consistently, Nox4-mediated ROS generation and fibrotic gene expression were attenuated upon Brd4 inhibition. Further, the transcriptional activity of Nox4 was suppressed by JQ1 or siRNA against Brd4. Additionally, Smad3 and ERK1/2 phosphorylation, which are upstream signals of Nox4 expression, were inhibited both in JQ1-administered UUO rats and Brd4-inhibited HK-2 cells. In conclusion, these results indicated that the inhibition of Brd4 might protect against renal fibrosis by blocking the TGF-β-Nox4-ROS-fibrosis axis, suggesting that Brd4 could be a promising therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression

Zhou

Gong

et al. 2017

Redox Biology

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“…The epigenetic landscape of renal injury is just starting to be described, particularly in the interstitium (114–115). Examples relevant to LN include chromatin structure modifications that regulate the production of CCL2 and TNF, DNA demethylation that regulates C3 production and histone acetylation that regulates the production of PDGF and pro-fibrotic genes (115).…”

Section: Identifying Novel Pathways That Contribute To Initiation Andmentioning

confidence: 99%

“…Examples relevant to LN include chromatin structure modifications that regulate the production of CCL2 and TNF, DNA demethylation that regulates C3 production and histone acetylation that regulates the production of PDGF and pro-fibrotic genes (115). Histone deacetylase inhibitors alleviate progression in multiple models of renal injury and fibrosis by preventing cytokine release and cell apoptosis and by inducing the protective molecule BMP-7 (116–117).…”

Section: Identifying Novel Pathways That Contribute To Initiation Andmentioning

confidence: 99%

What is damaging the kidney in lupus nephritis?

2015

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Summary Despite marked improvements in the survival of patients with severe lupus nephritis over the last 50 years the rate of complete clinical remission following immune suppression is less than 50% and renal impairment still occurs in 40% of affected patients. An appreciation of factors leading to the development of chronic kidney disease (CKD) following acute or subacute renal injury in lupus patients is beginning to emerge. Processes that contribute to endstage renal injury include continuing inflammation, activation of intrinsic renal cells, cell stress and hypoxia, metabolic abnormalities, aberrant tissue repair and tissue fibrosis. This understanding is leading to the development of novel or adjunctive therapies that may protect from the secondary non-immune consequences of acute injury. Approaches based on a molecular/proteomic/lipidomic classification of disease should yield new information about the functional basis of disease heterogeneity so that the most effective and least toxic treatment regimens can be formulated for individual patients.

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“…[17][18][19][20][21] However, there is no consensus regarding reliable monitoring and therapeutic strategies for patients with recovered from AKI and they can be the most easily ignored. As a result, more efforts are needed to clarify the mechanisms of AKI-CKD transition and multiple animal studies have displayed some plausible pathogenesis, such as a maladaptive repair induced by pericyte-myofibroblast transition, 22,23 profibrogenic cytokine production by G2/M cell-cycle arrested tubular cells, 22,24,25 epigenetic changes in myofibroblasts [26][27][28][29][30] and microvascular rarefaction. 23,[31][32][33] Nevertheless, the underlying mechanisms of clinical AKI-CKD continuum remain incompletely discovered.…”

Section: Introductionmentioning

confidence: 99%

Role of renin‐angiotensin system in acute kidney injury‐chronic kidney disease transition

2018

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Acute kidney injury (AKI) can increase the risk of developing incident chronic kidney disease (CKD). The severity, frequency and duration of AKI are crucial predictors of poor renal outcome. A repair process after AKI can be adaptive and kidney recovers completely after a mild injury. However, severe injury will lead to a maladaptive repair, which frequently progresses to nephron loss, vascular rarefaction, chronic inflammation and fibrosis. Although different mechanisms underlying AKI‐CKD transition have been extensively discussed, no definite intervention has been proved effective to block or to retard the transition until recently. In CKD, renin‐angiotensin system (RAS) inhibitor has been proved effective to slow down disease progression. Furthermore, RAS needs to be highlighted again in AKI‐CKD transition because recent animal studies have shown the activation of intra‐renal RAS after AKI, and RAS blockade can reduce the ensuing CKD and mortality. In patients with the complete renal recovery after AKI, administration of RAS inhibitor is associated with reduced risk of subsequent CKD as well. In this article, we will demonstrate the role of RAS in AKI‐CKD transition comprehensively. We will then emphasize the promising effect of RAS inhibitor on CKD prevention in patients recovering from AKI based on evidence from the bench to clinical research. All of these discussions will contribute to the establishment of reliable monitoring and therapeutic strategies for patients with functional recovery from AKI who can be most easily ignored.

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Epigenetic regulation in the acute kidney injury to chronic kidney disease transition

Cited by 45 publications

References 63 publications

Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression

Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression

What is damaging the kidney in lupus nephritis?

Role of renin‐angiotensin system in acute kidney injury‐chronic kidney disease transition

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