Acylated Ghrelin Protects Against Doxorubicin-Induced Kidney Damage by Activating SIRT1
Background
Doxorubicin (DOX) is a potent chemotherapy agent, but its use is often limited by severe side effects, including doxorubicin-induced nephropathy, a form of kidney damage. The underlying mechanisms involve oxidative stress, inflammation, and apoptosis, leading to fibrosis and functional decline. Current treatments are primarily supportive, creating a need for targeted therapies that can mitigate this toxicity. Acylated ghrelin (AG), an endogenous peptide hormone, is known for its anti-inflammatory and antioxidant properties. This study investigates whether AG can protect the kidneys from DOX-induced injury and explores the role of the SIRT1 pathway, a critical regulator of cellular stress responses and longevity, in mediating these potential protective effects.
Study Design
The study used a rat model to investigate the nephroprotective effects of acylated ghrelin (AG). Rats were divided into six groups: control, control + AG, DOX, DOX + AG, DOX + AG + [D-Lys3]-GHRP-6 (a ghrelin receptor antagonist), and DOX + AG + EX-527 (a SIRT1 inhibitor). Doxorubicin was administered over the first two weeks to induce nephropathy. Acylated Ghrelin (10 ng/kg), along with the inhibitors, was administered as three doses per week for a total of five weeks. The researchers assessed kidney structure and function, and measured renal expression levels of various biomarkers related to fibrosis, oxidative stress, inflammation, and apoptosis.
Results
Acylated ghrelin administration significantly ameliorated doxorubicin-induced kidney damage. It improved both the structure and function of the kidneys in DOX-treated rats. The treatment down-regulated the renal expression of profibrotic markers TGF-β1, collagen 1A1, and α-SMA, and inhibited renal collagen deposition. Furthermore, AG reduced renal levels of reactive oxygen species (ROS), malondialdehyde (MDA), and pro-inflammatory cytokines TNF-α and IL-6. It also decreased levels of apoptosis-related proteins cytochrome-c, cleaved caspase-3, and Bax, while increasing antioxidant levels of SOD and GSH.
Most importantly, AG increased the total levels and nuclear activity of
SIRT1and reduced the deacetylation of its targetsp53,NF-κB, andFOXO-31. All of these protective effects were completely abolished by the co-administration of either theSIRT1inhibitor EX-527 or the ghrelin receptor antagonist [D-Lys3]-GHRP-6.
Key Findings
- Acylated ghrelin (AG) improved kidney structure and function in rats treated with doxorubicin (DOX).
- AG reduced renal levels of oxidative stress markers (ROS, MDA) and inflammatory cytokines (TNF-α, IL-6).
- AG down-regulated profibrotic markers including TGF-β1, collagen 1A1, and α-SMA.
- The protective effects of AG were mediated by increased levels and nuclear activity of SIRT1.
- All benefits of AG were abolished by a ghrelin receptor antagonist or a SIRT1 inhibitor, confirming the mechanism.
Why It Matters
This research provides a strong preclinical rationale for using acylated ghrelin as a potential adjunctive therapy to mitigate the kidney damage caused by doxorubicin chemotherapy. For individuals undergoing DOX treatment, this could mean better preservation of kidney function and improved tolerance of the chemotherapy regimen. The findings highlight a specific mechanism of action involving both the ghrelin receptor (GHS-R1a) and the SIRT1 pathway, offering clear targets for future drug development. The results suggest that protecting the SIRT1 pathway is a critical component of acylated ghrelin's nephroprotective effect. While this is a promising animal study, clinical trials in humans are necessary to determine the safety, effective dosage, and timing for using ghrelin or related agonists to prevent chemotherapy-induced nephropathy. This study does not yet provide a usable human protocol.
