Inhibition of p300/CBP-Associated Factor Attenuates Renal Tubulointerstitial Fibrosis through Modulation of NF-kB and Nrf2

Chung, Sungjin; Kim, Soo-Jeong; Son, Min Jung; Kim, Minyoung; Koh, Eun Sil; Shin, Seok Joon; Park, Cheol Whee; Kim, Ho‐Shik

doi:10.3390/ijms20071554

Cited by 48 publications

(44 citation statements)

References 41 publications

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“…IL-6 also has been shown to play an important role in cisplatin-induced inflammation [ 50 ]. Consistent with our findings, previous studies have shown that garcinol suppressed cytokine production in lipopolysaccharide-stimulated microglia [ 48 ], IL-1β-treated chondrocytes [ 30 ], and kidneys from mice subjected to unilateral ureteral obstruction [ 51 ]. In addition, we found that administration of garcinol suppressed accumulation of neutrophils and macrophages along with downregulation of chemokines and vascular adhesion molecules.…”

Section: Discussionsupporting

confidence: 93%

Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice

Kim

Leem

et al. 2020

Antioxidants

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Emerging evidence suggests that epigenetic mechanisms such as histone modification are crucially involved in the pathophysiology of acute kidney injury (AKI). The histone acetyltransferase p300 regulates several biological processes through the acetylation of histones or transcription factors. However, the role of p300 in cisplatin-induced AKI remains poorly understood. Therefore, we investigated the effects of garcinol, a potent p300 inhibitor, on cisplatin-induced AKI and explored the mechanisms. Administration of garcinol significantly reversed the upregulation of p300 and increased acetylation of histone H3, along with amelioration of renal dysfunction and histopathological injury in the kidneys of cisplatin-injected mice. Garcinol also attenuated oxidative stress and reduced expression of pro-oxidant enzymes. In addition, garcinol reduced the elevated production of cytokines and chemokines and suppressed immune cell accumulation together with downregulation of vascular adhesion molecules. These beneficial effects of garcinol were associated with a reduction in acetylation of the p65 subunit of nuclear factor kappa-B. Further, garcinol significantly inhibited apoptosis and caspase-3 activation, with a decrease in p53 acetylation in cisplatin-injected mice. Taken together, we demonstrated that the inhibition of p300 by garcinol ameliorated cisplatin-induced renal injury, presumably through epigenetic mechanisms. These results suggest that garcinol might be a potential preventive agent for cisplatin-induced AKI.

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Section: Discussionsupporting

confidence: 93%

Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice

Kim

Leem

et al. 2020

Antioxidants

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“…Oxidative stress is an imbalance between the oxidation system and the endogenous antioxidant defense system that results in ATP depletion. As described in previous reports, UUO is linked to reduced levels of the antioxidative enzymes SOD1 and Catalase [44,45]. Our findings confirmed these results, as detected by Western blot of in vivo samples and DCFH-DA probe analysis of in vitro samples.…”

Section: Discussionsupporting

confidence: 93%

Extracellular vesicles produced by bone marrow mesenchymal stem cells attenuate renal fibrosis, in part by inhibiting the RhoA/ROCK pathway, in a UUO rat model

Shi

Wang

Zhang

et al. 2020

Preprint

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Background Renal interstitial fibrosis is a critical symptom of chronic kidney disease (CKD) that is associated with high incidence. Extracellular vesicles produced by bone marrow mesenchymal stem cells (BMSC-EVs) can play important roles in the repair of injured tissues. However, no reports have investigated the role and mechanism of BMSC-EVs in renal fibrosis. Thus, we hypothesized that BMSC-EVs containing milk fat globule-EGF factor-8 (MFG-E8) could attenuate renal fibrosis by inhibiting the RhoA/ROCK pathway.Methods We investigated whether BMSC-EVs have antifibrotic effects in a rat model of renal fibrosis-rats subjected to unilateral ureteral obstruction (UUO) - as well as in cultured HK2 cells. In vivo, Sprague-Dawley (SD) rats were randomly divided into 6 groups: Sham group, Sham + EVs group, UUO group, UUO + EVs group, UUO + EVs Ctrl group, and UUO + EVs shMFGE8 group. In vitro, extracellular vesicles from BMSCs were collected and co-cultured with HK2 cells during transforming growth factor-β1 (TGF-β1) treatment. Besides, HK2 cells co-cultured with TGF-β1 were also treated with the ROCK inhibitor, Y-27632. Results Compared with the Sham group, UUO rats displayed fibrotic abnormalities, accompanied by increased expression of α-SMA and Fibronectin, and decreased expression of E-cadherin. Both molecular and pathological changes suggested an increased inflammation in damaged kidneys. Oxidative stress, as evidenced by decreased levels of SOD1 and Catalase, was also observed in UUO kidneys. In addition, activation of cleaved caspase-3 and PARP1 and increased apoptosis in the proximal tubules confirmed tubular cell apoptosis in the UUO group. All of these phenotypes exhibited by UUO rats were suppressed by treatment with BMSC-EVs. However, the protective effect of BMSC-EVs was completely abolished by inhibition of MFG-E8. Consistent with the in vivo results, treatment with BMSC-EVs reduced inflammation, oxidative stress, apoptosis, and fibrosis in HK-2 cells stimulated with TGF-β1 in vitro . Interestingly, treatment with Y-27632, a ROCK inhibitor, protected HK-2 cells against inflammation and fibrosis, although oxidative stress and apoptosis were unchanged. Conclusions In summary, our results show that BMSC-EVs containing MFG-E8 attenuate renal fibrosis, partly through RhoA/ROCK pathway inhibition.

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“…More importantly, NF- κ B, a key factor of inflammatory signaling, could once be phosphorylated and enter into the nucleus, activating the genes of inflammatory and fibrogenic factors. It has been reported that NF- κ B signaling was activated in UUO models, and the blockade of NF- κ B signaling would improve renal fibrosis [ 34 , 35 ]. Our results found significantly elevated protein levels of P65, p-P65, and p-i κ B α and decreased level of i κ B α in UUO rats, whereby hirudin efficiently reversed these changes.…”

Section: Discussionmentioning

confidence: 99%

Hirudin Ameliorates Renal Interstitial Fibrosis via Regulating TGF‐β1/Smad and NF‐κB Signaling in UUO Rat Model

Yang

Fan

Zhao

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Purpose. Hirudin, a polypeptide structure containing 65 amino acids, is a potent natural thrombin inhibitor with anticoagulant property extracted from Hirudo medicinalis. It has been reported to have anti-inflammatory and antifibrotic property. Here we explored the renoprotective effect of hirudin on unilateral ureteral obstruction (UUO) induced renal interstitial fibrosis (RIF). Methods. Rats were randomly divided into five groups: sham group, UUO alone group, and three UUO + hirudin-treatment groups (10, 20, or 40 IU/kg/d, for 14 continuous days). At the end of the experiment period, animals were sacrificed. Pathologic changes in renal specimens were observed using hematoxylin and eosin (HE) staining and Masson staining. The expressions of collagen III (Col III), fibronectin (FN), α-smooth muscle actin (α-SMA), protease-activated receptor 1 (PAR-1), and proteins in the TGF-β1/Smad and NF-κB pathways in renal tissues were examined by immunohistochemistry and/or Western blotting. Results. HE and Masson staining showed that hirudin-treated UUO rats had lower extent of renal injury and deposition of extracellular matrix (ECM) in renal interstitium than those in the UUO group. The results of immunohistochemistry and WB indicated decreased protein expressions of Col III, FN, α-SMA, PAR-1, and inflammatory markers such as tumor necrosis factor-α and interleukin-6 after hirudin treatment. Furthermore, hirudin reduced the expressions of transforming growth factor β1 (TGF-β1), phosphorylated-Smad2, and phosphorylated-Smad3 in the UUO model. In parallel, we found inhibited nuclear factor-κB (NF-κB) signaling after hirudin treatment, with downregulated protein expressions of P65, phosphorylated-P65, and phosphorylated-iκBα and increased iκBα. Conclusion. Hirudin improves kidney injury and suppresses inflammatory response and ECM accumulation in UUO rats; its underlying mechanism may be associated with the inhibition of TGF-β1/Smad and NF-κB signaling.

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Inhibition of p300/CBP-Associated Factor Attenuates Renal Tubulointerstitial Fibrosis through Modulation of NF-kB and Nrf2

Cited by 48 publications

References 41 publications

Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice

Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice

Extracellular vesicles produced by bone marrow mesenchymal stem cells attenuate renal fibrosis, in part by inhibiting the RhoA/ROCK pathway, in a UUO rat model

Hirudin Ameliorates Renal Interstitial Fibrosis via Regulating TGF‐β1/Smad and NF‐κB Signaling in UUO Rat Model

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