Mechanistic Approach for Protective Effect of ARA290, a Specific Ligand for the Erythropoietin/CD131 Heteroreceptor, against Cisplatin-Induced Nephrotoxicity, the Involvement of Apoptosis and Inflammation Pathways.
Ghassemi-Barghi. Nasrin N; Ehsanfar. Zeynab Z; Mohammadrezakhani. Omid O; Ashari. Sorour S; Ghiabi. Shamim S; Bayrami. Zahra Z
Key Findings
- ARA290 reduced DNA damage and micronucleus formation caused by cisplatin in kidney cell lines.
- The peptide lowered oxidative stress markers (ROS, MDA) and boosted antioxidant enzymes (GPx, SOD).
- Inflammatory cytokines (TNFα, IL‑1β, IL‑6) and pro‑apoptotic proteins (caspase‑3, Bax) were decreased, while the anti‑apoptotic protein Bcl‑2 increased.
Practical Outcomes
- For biohackers, the data suggest ARA290 has strong anti‑oxidant, anti‑inflammatory, and anti‑apoptotic properties that could be useful for protecting kidneys or other tissues from toxic insults. However, the study was done in cell cultures with nanomolar doses, and no human dosing or safety information is provided, so it isn’t ready for direct self‑administration. If ARA290 becomes available, it might be explored as a low‑dose adjunct for kidney support, but more research is needed before practical protocols can be recommended.
Summary
In lab tests, the short peptide ARA290 helped kidney cells avoid damage from the chemotherapy drug cisplatin. It did this by cutting down harmful oxidative stress, lowering inflammation signals, and stopping cells from dying through apoptosis. The study shows ARA290 can act like a protective shield for kidneys under toxic stress.
Abstract
ARA 290, an 11-amino acid linear nonhematopoietic peptide derived from the three-dimensional structure of helix B of the erythropoietin (EPO), interacts selectively with the innate repair receptor (IRR) that arbitrates tissue protection. The aim of this study was to investigate the protective effects of ARA290 against cisplatin-induced nephrotoxicity. For this purpose, HEK-293 and ACHN cells were treated with ARA290 (50-400 nM) and cisplatin (2.5 μM) in pretreatment condition. Then, cytotoxicity, genotoxicity, oxidative stress parameters (ROS, GPx, SOD, and MDA), and inflammatory markers (TNFα, IL6, and IL1β) were evaluated. Furthermore, apoptotic cell death was assessed via caspase-3 activity and tunnel assay. To determine the molecular mechanisms of the possible nephroprotective effects of ARA290, gene and protein expressions of TNFα, IL1β, IL6, Caspase-3, Bax, and Bcl2 were evaluated by real-time PCR and western blot assay, respectively. The findings indicated that ARA290 significantly reduced the DNA damage parameters of comet assay and the frequency of micronuclei induced by cisplatin. Besides, ARA290 improved cisplatin-induced oxidative stress by reducing MDA/ROS levels and enhancing antioxidant enzyme levels. In addition, reduced levels of pro-inflammatory cytokines indicated that cisplatin-induced renal inflammation was mitigated upon the treatment with ARA290. Besides, ARA290 ameliorates cisplatin-induced cell injury by antagonizing apoptosis. Furthermore, the molecular findings indicated that gene and protein levels of TNFα, IL1β, IL6, Caspase-3, and Bax were significantly decreased and gene and protein levels of Bcl2 significantly increased in the ARA290 plus cisplatin group compared with the cisplatin group. These findings revealed that ARA290 as a potent chemo-preventive agent exerted a protective effect on cisplatin-induced nephrotoxicity mostly through its anti-apoptotic, anti-inflammatory, and antioxidant potentials and also suggested that ARA290 might be a new therapeutic approach for patients with acute kidney injury.
Study Information
pubmed
2022
2022-09-10T00:00:00.000Z
10.1007/s10753-022-01737-7
9
75