Peptide DR8 suppresses epithelial-to-mesenchymal transition via the TGF-β/MAPK signaling pathway in renal fibrosis

Deng, Bochuan; Yang, Wenle; Wang, Dan; Cheng, Lü; Bu, Lili; Rao, Jing; Zhang, Jianfeng; Xie, Junqiu; Zhang, Bangzhi

doi:10.1016/j.lfs.2020.118465

Cited by 26 publications

(14 citation statements)

References 39 publications

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“…It has also been reported that intratracheal instillation of 2-5 mg/kg BLM alone can induce PF in C57BL/6 mice (Li et al, 2021). As reported in previous studies, 5 mg/kg BLM can effectively and significantly induce PF, and subcutaneous injection of DR8 and DR8 analogs (0.5 mg/kg/d) showed good antifibrotic activity, low toxicity and few effects at this dose (Deng et al, 2020;Wang et al, 2021;Wang et al, 2019). Therefore, the same experimental scheme was performed, and 0.5 and 2.5 mg/kg/d were determined as the dosage regimen of DR7dA in this experiment.…”

Section: Animals and Treatmentssupporting

confidence: 71%

“…(DHNNPQIR-NH 2 ) can block the progression of PF and renal fibrosis (Deng et al, 2020;Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Since replacing L-amino acids with nonnatural D-amino acids can improve stability and since D-Ala is readily available, we chose to replace the Ile of DR8 with D-Ala. To investigate whether the modified peptide has greater stability in serum and retains the antifibrotic activity of the parent peptide, a TGF-β1-induced cell 10 find that 1-10 ng/mL TGF-β1 was used to induce cell models, and many results show that 5 ng/mL TGF-β1 can be successfully used to construct cell models (Ji et al, 2018;Wang et al, 2016). Similarly, 1-10 ng/mL TGF-β1 was selected to treat cells in previous studies, and the results showed that 5 ng/mL TGF-β1 can stably and effectively induce cell fibrogenesis, such as cell proliferation, EMT, morphologic changes, and high expression of fibrosis-related genes and proteins (Deng et al, 2020;Wang et al, 2021;Wang et al, 2019). Therefore, 5 ng/mL TGF-β1 was used in this study.…”

Section: Introductionmentioning

confidence: 99%

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DR7dA, a Novel Antioxidant Peptide Analog, Demonstrates Antifibrotic Activity in Pulmonary Fibrosis In Vivo and In Vitro

Cheng

Wang

Deng

et al. 2022

J Pharmacol Exp Ther

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Pulmonary fibrosis (PF), which is characterized by enhanced extracellular matrix (ECM) deposition, is an interstitial lung disease that lacks an ideal clinical treatment strategy. It has an extremely poor prognosis, with an average survival of 3-5 years after diagnosis. Our previous studies have shown that the antioxidant peptide DR8 (DHNNPQIR-NH 2 ), which is extracted and purified from rapeseed, can alleviate PF and renal fibrosis. However, natural peptides are easily degraded by proteases in vivo, which limits their potency. We have since synthesized a series of DR8 analogs based on amino acid scanning substitution. DR7dA (DHNNPQ (D-alanine) R-NH 2 ) is an analog of DR8 in which L-isoleucine (L-Ile) is replaced with D-alanine (D-Ala), and its half-life is better than that of DR8. In the current study, we verified that DR7dA ameliorated TGF-β1-induced fibrogenesis and bleomycin-induced PF. The results indicated that DR7dA reduced the protein and mRNA levels of TGF-β1-target genes in TGF-β1-induced models. Surprisingly, DR7dA blocked fibrosis in a lower concentration range than DR8 in cells. In addition, DR7dA ameliorated tissue pathological changes and ECM accumulation in mice. BLM caused severe oxidative damage, but administration of DR7dA reduced oxidative stress and restored antioxidant defense. Mechanistic studies suggested that DR7dA inhibits ERK, P38 and JNK phosphorylation in vivo and in vitro. All results indicated that DR7dA attenuated PF by inhibiting ECM deposition and oxidative stress via blockade of the MAPK pathway. Hence, compared with its parent peptide, DR7dA has higher druggability and could be a candidate compound for PF treatment in the future.

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Section: Animals and Treatmentssupporting

confidence: 71%

“…(DHNNPQIR-NH 2 ) can block the progression of PF and renal fibrosis (Deng et al, 2020;Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DR7dA, a Novel Antioxidant Peptide Analog, Demonstrates Antifibrotic Activity in Pulmonary Fibrosis In Vivo and In Vitro

Cheng

Wang

Deng

et al. 2022

J Pharmacol Exp Ther

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“…In folic-acid-induced AKI, 24 h after folic acid administration, mitochondrial MDA and 4-HNE levels increase [44]. Both OS markers also increase in nephrectomy models [127,128]. Together, these results show that mitochondria suffer lipid peroxidation in AKI and AKI to CKD transition.…”

Section: Oxidation and Os Production And In Kidney Diseasesmentioning

confidence: 68%

Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

et al. 2021

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Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.

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“…These transcription factors can inhibit E-cadherin and induce the expression of TGF-β receptors. The MAPK and TGF-β signaling pathways jointly promote the progression of EMT [ 95 ]. In addition, studies have shown that the composition of snail and CREB-binding protein (CBP) can stimulate the inflammatory response to renal fibrosis [ 96 ] (Fig.…”

Section: Signaling Pathway In Renal Fibrosismentioning

confidence: 99%

Stem cells in the treatment of renal fibrosis: a review of preclinical and clinical studies of renal fibrosis pathogenesis

Liu

Yang

et al. 2021

Stem Cell Res Ther

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Renal fibrosis commonly leads to glomerulosclerosis and renal interstitial fibrosis and the main pathological basis involves tubular atrophy and the abnormal increase and excessive deposition of extracellular matrix (ECM). Renal fibrosis can progress to chronic kidney disease. Stem cells have multilineage differentiation potential under appropriate conditions and are easy to obtain. At present, there have been some studies showing that stem cells can alleviate the accumulation of ECM and renal fibrosis. However, the sources of stem cells and the types of renal fibrosis or renal fibrosis models used in these studies have differed. In this review, we summarize the pathogenesis (including signaling pathways) of renal fibrosis, and the effect of stem cell therapy on renal fibrosis as described in preclinical and clinical studies. We found that stem cells from various sources have certain effects on improving renal function and alleviating renal fibrosis. However, additional clinical studies should be conducted to confirm this conclusion in the future.

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Peptide DR8 suppresses epithelial-to-mesenchymal transition via the TGF-β/MAPK signaling pathway in renal fibrosis

Cited by 26 publications

References 39 publications

DR7dA, a Novel Antioxidant Peptide Analog, Demonstrates Antifibrotic Activity in Pulmonary Fibrosis In Vivo and In Vitro

DR7dA, a Novel Antioxidant Peptide Analog, Demonstrates Antifibrotic Activity in Pulmonary Fibrosis In Vivo and In Vitro

Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

Stem cells in the treatment of renal fibrosis: a review of preclinical and clinical studies of renal fibrosis pathogenesis

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