Regeneration after acute kidney injury requires PTIP-mediated epigenetic modifications

Soofi, Abdul; Kutschat, Ana P.; Azam, Mohammad; Laszczyk, Ann M.; Dressler, Gregory R.

doi:10.1172/jci.insight.130204

Cited by 20 publications

(23 citation statements)

References 60 publications

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“…In addition, adaptive tubular repair is an important process to delay AKI progression, and tubular cell regeneration is a key event (Basile et al, 2016). It has been reported that fully differentiated tubular cells have equal chances of proliferation after injury (Humphreys et al, 2016;Soofi et al, 2020). In our study, increased cell proliferation was observed in the FG-4592treated mice, indicating the stimulation of tubular repair.…”

Section: Discussionsupporting

confidence: 60%

“…Therefore, it is essential to explore the possible mechanisms and seek novel therapeutic options involving maximization of kidney repair to ameliorate AKI prognosis (Lin and Hsu 2020). The regenerative capacity of tubules is limited; in comparison, tubular cells have more regenerative capacity after injury, although the mechanisms are unknown (Soofi et al, 2020). Moreover, maladaptive repair could lead to CKD, which is closely related to cell death and continuous inflammation, eventually leading to increased extracellular matrix accumulation (Gibbs et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

et al. 2022

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Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

et al. 2022

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“…In a recent study, it was observed that indeed, epigenetic modifications occur early after folic acid-induced kidney damage. In particular, it was observed that de novo methylation of histone H3K4 is necessary for the differentiated cells to re-enter mitosis and regenerate the proximal tubular epithelium 63 . These findings together, highlighted the crucial role of the early epigenetic modifications in the long consequences after an ischemic insult.…”

Section: Discussionmentioning

confidence: 99%

Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia

Sánchez‐Navarro

Pérez‐Villalva

Murillo‐de‐Ozores

et al. 2021

Sci Rep

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Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.

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“…Recent studies show that epigenetic factors can modulate nephron progenitor cell renewal and differentiation during development ( Liu et al., 2018 , 2020 ; Wanner et al., 2019 ). Furthermore, progression of acute kidney injury (AKI) and chronic kidney disease (CKD) can be modulated by epigenetic factors such as DNA methylation and histone modifications, some of which persist after AKI and likely promote fibrosis and CKD ( Liu et al., 2017 ; Chawla et al., 2014 ; Ferenbach and Bonventre, 2015 ; Sharifian et al., 2018 ; Soofi et al, 2020 ). Recently, activating chromatin marks such as histone K4 trimethylation were shown to be dynamically regulated after kidney injury and play key roles in activating reparative programs such as Sox9 expression in mice (Soofi et al., 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, progression of acute kidney injury (AKI) and chronic kidney disease (CKD) can be modulated by epigenetic factors such as DNA methylation and histone modifications, some of which persist after AKI and likely promote fibrosis and CKD (Liu et al, 2017;Chawla et al, 2014;Ferenbach and Bonventre, 2015;Sharifian et al, 2018;Soofi et al, 2020). Recently, activating chromatin marks such as histone K4 trimethylation were shown to be dynamically regulated after kidney injury and play key roles in activating reparative programs such as Sox9 expression in mice (Soofi et al, 2020). Our data suggest that the Acomys genome is poised to initiate scarless wound healing at the time of kidney injury.…”

Section: Complete Regeneration Of Kidney Function After Iri In Acomysmentioning

confidence: 99%

Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis

Okamura

Brewer

Wakenight³

et al. 2021

iScience

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Regeneration after acute kidney injury requires PTIP-mediated epigenetic modifications

Cited by 20 publications

References 60 publications

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia

Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis

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