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Multi-Pathway Renoprotection by Betanin Against Docetaxel Nephrotoxicity: Modulation of Inflammation, ER Stress,
Büşra Süzen Celbek1, Nurhan Akaras2, Hasan Şimşek3
1Department of Pediatrics, Liv Hospital Ankara, Ankara, Türkiye.
Abstract:
Docetaxel (DTX), a cornerstone chemotherapeutic agent, has its clinical utility significantly limited by dose-dependent nephrotoxicity. This study investigated the multi-pathway renoprotective mechanisms of betanin (BTN), a natural antioxidant derived from beetroot, against DTX-induced kidney injury. Male Wistar rats received DTX (30 mg/kg, i.p., single dose) with or without BTN (100 mg/kg/day, p.o.) for 7 days. DTX induced severe renal dysfunction with elevated serum urea and creatinine, and significant oxidative stress characterized by increased MDA and decreased GSH, GPx, SOD, and CAT. Molecular analysis demonstrated widespread upregulation of pro-inflammatory (NF-κB, TNF-α, IL-1β), endoplasmic reticulum stress (PERK, ATF6), pro-apoptotic (Caspase-3, Bax, Apaf-1), and pro-ferroptotic (PTGS2, TfR1) mediators, with concurrent downregulation of protective Bcl-2 and GPx4. Histopathological examination revealed extensive tubular injury, while immunohistochemical analysis showed markedly increased kidney injury marker KIM-1 and decreased aquaporin-1 expression. Remarkably, BTN co-administration significantly attenuated all biochemical, molecular, and structural derangements, restored tissue architecture, and normalized KIM-1 and AQP-1 expression. In conclusion, betanin provides robust, multi-pathway renoprotection against docetaxel-induced nephrotoxicity by concurrently targeting oxidative stress, inflammation, ER stress, apoptosis, and ferroptosis.
Insights
Betanin (BTN), a beetroot antioxidant, protects against docetaxel (DTX)-induced kidney injury. BTN targets multiple pathways including oxidative stress, inflammation, and cell death, offering significant renoprotection.
Area of Science:
- Pharmacology
- Toxicology
- Natural Product Chemistry
Background:
- Docetaxel (DTX) chemotherapy causes dose-dependent nephrotoxicity, limiting its clinical use.
- Kidney injury involves complex mechanisms including oxidative stress, inflammation, and cell death pathways.
Purpose of the Study:
- To investigate the renoprotective effects of betanin (BTN), a natural antioxidant from beetroot, against DTX-induced kidney injury.
- To elucidate the multi-pathway mechanisms underlying BTN's protective action.
Main Methods:
- Male Wistar rats were treated with DTX alone or in combination with BTN.
- Biochemical markers (serum urea, creatinine), oxidative stress indices (MDA, GSH, GPx, SOD, CAT), molecular mediators (pro-inflammatory, ER stress, apoptotic, ferroptotic markers), and histopathology were assessed.
- Immunohistochemistry was used to evaluate kidney injury marker 1 (KIM-1) and aquaporin-1 (AQP-1) expression.
Main Results:
- DTX induced significant renal dysfunction, oxidative stress, inflammation, ER stress, apoptosis, and ferroptosis.
- Histopathology showed severe tubular injury, increased KIM-1, and decreased AQP-1 expression.
- BTN co-administration markedly attenuated these DTX-induced derangements, restoring normal biochemical, molecular, and structural parameters.
Conclusions:
- Betanin exhibits potent, multi-pathway renoprotective effects against docetaxel-induced nephrotoxicity.
- BTN's protective action involves concurrent targeting of oxidative stress, inflammation, ER stress, apoptosis, and ferroptosis, highlighting its therapeutic potential.
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