Therapeutic treatment with phosphodiesterase-4 inhibitors alleviates kidney injury and renal fibrosis by increasing MMP-9 in a doxorubicin-induced nephrotoxicity mouse model

Costa, Walyson Coelho; Beltrami, Vinícius Amorim; Campolina-Silva, Gabriel Henrique; Queiroz-Júnior, Celso Martins; Florentino, Rodrigo M.; Machado, Jéssica Rayssa; Martins, Débora Gonzaga; Gonçalves, William; Barroso, Lívia Corrêa; Freitas, Kátia Michelle; Souza-Neto, Fernando Pedro de; Félix, Franciel Batista; Silva, Rafaela da; Oliveira, Cleida A.; Câmara, Niels Olsen Saraiva; Rachid, Milene Alvarenga; Teixeira, Mauro Martins; Rezende, Bárbara Antunes; Pinho, Vanessa

doi:10.1016/j.intimp.2022.109583

Cited by 5 publications

(3 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, farnesol inhibited CCL2, which is also known as monocyte chemoattractant protein-1 (MCP-1), the most prominent chemokine-promoting tissue fibrosis [47]. The therapeutic inhibitors of renal fibrosis were shown to downregulate the expression of CCL2 in renal cells [48,49]. These observations are in line with our findings and may be the mechanism by which farnesol protects against renal inflammation and fibrosis.…”

Section: Discussionsupporting

confidence: 89%

Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells

Müller,

Lozoya,

Chen

et al. 2023

Biomedicines

View full text Add to dashboard Cite

Chronic inflammation and elevated cytokine levels are closely associated with the progression of chronic kidney disease (CKD), which is responsible for the manifestation of numerous complications and mortality. In addition to conventional CKD therapies, the possibility of using natural compounds with anti-inflammatory potential has attracted widespread attention in scientific research. This study aimed to study the potential anti-inflammatory effects of a natural oil compound, farnesol, in primary human renal proximal tubule epithelial cell (RPTEC) culture. Farnesol was encapsulated in lipid-based small unilamellar vesicles (SUVs) to overcome its insolubility in cell culture medium. The cell attachment of empty vesicles (SUVs) and farnesol-loaded vesicles (farnesol-SUVs) was examined using BODIPY, a fluorescent dye with hydrophobic properties. Next, we used multiple protein, RNA, and protein phosphorylation arrays to investigate the impact of farnesol on inflammatory signaling in RPTECs. The results indicated that farnesol inhibits TNF-α/IL-1β-induced phosphorylation of the PI3 kinase p85 subunit and subsequent transcriptional activation of the inflammatory genes TNFRSF9, CD27, TNFRSF8, DR6, FAS, IL-7, and CCL2. Therefore, farnesol may be a promising natural compound for treating CKD.

show abstract

Section: Discussionsupporting

confidence: 89%

Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells

Müller,

Lozoya,

Chen

et al. 2023

Biomedicines

View full text Add to dashboard Cite

show abstract

“…cAMP is the classic second messager, which could activate PKA/CREB cascade pathway or be hydrolyzed into AMP by PDE4 [ 42 ]. Recently, the serial work suggested PDE4 could be a promising therapeutic target for various diseases, such as nephrotic syndrome [ 43 ], acute myeloid leukemia [ 44 ], idiopathic pulmonary fibrosis [ 45 ], heart failure [ 46 ], and colitis [ 8 ]. Interestingly, phosphorylation of PDE4 is a critical event in VTN-induced ferroptosis and dysfunction of cell differentiation, as confirmed by the results that inhibition of PDE4 by DIP could alleviate the effect of VTN on ferroptosis-dependent cell differentiation in IECs, and DIP administration could drastically improve CDX2-mediated cell differentiation in an animal model and in a pilot study.…”

Section: Discussionmentioning

confidence: 99%

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease

Pan

Liang

et al. 2023

Mediators of Inflammation

View full text Add to dashboard Cite

Objective. Vitronectin (VTN) has been reported to trigger cell pyroptosis to aggravate inflammation in our previous study. However, the function of VTN in inflammatory bowel disease (IBD) remains to be addressed. Methods. Real-time PCR and western blotting were performed to analyze VTN-regulated intestinal epithelial cell (IEC) differentiation through ferroptosis, and immunofluorescence (IF), luciferase, and chromatin immunoprecipitation were used to identify whether VTN-modulated ferroptosis is dependent on phosphodiesterase 4 (PDE4)/protein kinase A (PKA)/cyclic adenosine monophosphate-response element-binding protein (CREB) cascade pathway. In vivo experiment in mice and a pilot study in patients with IBD were used to confirm inhibition of PDE4-alleviated IECs ferroptosis, leading to cell differentiation during mucosal healing. Results. Herein, we found that caudal-related homeobox transcription factor 2-mediated IECs differentiation was impaired in response to VTN, which was attributed to enhanced ferroptosis characterized by decreased glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 expression. Inhibition of ferroptosis in IECs rescued the inhibitory effect of VTN on cell differentiation. Further analysis showed that VTN triggered phosphorylation of PDE4, leading to inhibit PKA/CREB activation and CREB nuclear translocation, which further reduced GPX4 transactivation. Endogenous PKA interacted with CREB, and this interaction was destroyed in response to VTN stimulation. What is more, overexpression of CREB in CaCO2 cells overcame the promotion of VTN on ferroptosis. Most importantly, inhibition of PDE4 by roflumilast or dipyridamole could alleviate dextran sulfate sodium-induced colitis in mice and in a pilot clinical study confirmed by IF. Conclusions. These findings demonstrated that highly expressed VTN disrupted IECs differentiation through PDE4-mediated ferroptosis in IBD, suggesting targeting PDE4 could be a promising therapeutic strategy for patients with IBD.

show abstract

“…In various studies, the relationship between the use of anticancer drugs and kidney toxicity has been reported (6,7). Doxorubicin (DOX) is one of the anti-cancer drugs that is effective in treating various human cancers (8,9). Despite the good effectiveness of DOX in the treatment of several cancers, due to its toxic effects on some organs such as the kidneys, its therapeutic use is limited.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Transplantation Alleviates Doxorubicin-Induced Toxicity in Rat Renal Cells

Seydi,

Andalib,

Yaghoubi

et al. 2024

Iran J Pharm Res

View full text Add to dashboard Cite

Background: Doxorubicin (DOX) is used in the treatment of various cancers and has good effectiveness. However, its therapeutic use is limited due to its effects on various organs and healthy cells. Doxorubicin can affect the kidneys and cause toxicity. Evidence shows that DOX induces nephrotoxicity through oxidative stress. Objectives: In this research, we examined the effect of mitochondrial transplantation on improving mitochondrial and cellular toxicity caused by DOX on renal proximal tubular cells (RPTCs). Methods: The research measured 7 toxicity parameters, including cell lysis, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) decline, GSH and GSSG content, lipid peroxidation (LPO), adenosine triphosphate (ATP) content, and Caspase-3 activity (the final mediator of apoptosis). Active fresh mitochondria were prepared from Wistar rat kidney. Results: The findings indicated that DOX caused cytotoxicity in RPTCs. Additionally, DOX induced oxidative stress by increasing the level of reactive oxygen species, reducing glutathione content, and elevating lipid peroxidation. Moreover, it led to damage to the mitochondrial membrane, increased caspase-3 activity, and decreased ATP content. Mitochondrial transplantation, as a new therapeutic approach, reduced oxidative stress, mitochondrial membrane damage, and apoptosis caused by DOX in RPTCs. Furthermore, this therapeutic approach increased the ATP content in RPTCs. Conclusions: Our study suggests that this therapeutic approach could be helpful in the treatment of drug-induced nephrotoxicity.

show abstract

Therapeutic treatment with phosphodiesterase-4 inhibitors alleviates kidney injury and renal fibrosis by increasing MMP-9 in a doxorubicin-induced nephrotoxicity mouse model

Cited by 5 publications

References 88 publications

Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells

Farnesol Inhibits PI3 Kinase Signaling and Inflammatory Gene Expression in Primary Human Renal Epithelial Cells

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease

Mitochondrial Transplantation Alleviates Doxorubicin-Induced Toxicity in Rat Renal Cells

Contact Info

Product

Resources

About