Lactoferrin alleviates gentamicin-induced acute kidney injury in rats by suppressing ferroptosis: Highlight on ACSL4, SLC7A11, NCOA4, FSP1 pathways and miR-378a-3p, LINC00618 expression

• Published in: Food and chemical toxicology 2024-11, Vol.193, p.115027, Article 115027
• Main Authors: Salama, Rania M., Darwish, Samar F., Yehia, Rana, Sallam, Al Aliaa, Elmongy, Noura F., Abd-Elgalil, Mona M., El Wakeel, Sara A.
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Animals; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Ferroptosis; Ferroptosis - drug effects; Gentamicin; Gentamicins - adverse effects; Gentamicins - toxicity; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Lactoferrin; Lactoferrin - pharmacology; Male; MicroRNAs - genetics; MicroRNAs - metabolism; NCOA4; Rats; Rats, Sprague-Dawley; TFR1
• ISSN: 0278-6915; 1873-6351; 1873-6351
• DOI: 10.1016/j.fct.2024.115027

The use of gentamicin (GNT) is associated with acute kidney injury (AKI). Ferroptosis is a newly recognized iron-dependent, non-apoptotic cell death that can lead to AKI. Lactoferrin (LF), an iron-binding glycoprotein, was previously reported to be renoprotective. Nonetheless, LF's impact on GNT-induced AKI and ferroptosis has not yet been investigated. Accordingly, we assessed the dose-dependent effect of LF on GNT-induced AKI and its influence on ferroptosis. Thirty-six male rats were allocated as control, LF, GNT (100 mg/kg/day, i.p.), and groups given LF (100, 200, and 300 mg/kg, p.o.) for 14 days prior concurrently with GNT (Day 8–14). The high dose of LF (300 mg/kg) showed better histopathological picture, higher creatinine clearance, reduced serum and urine levels of kidney injury markers when compared to the GNT group and the lower two doses. These nephroprotective effects of LF can be attributed to the observed reduction in renal ferrous iron, 4-HNE, and MDA, miR-378a-3p and ALOX15 expression, TFR1, NCOA4, and ACSL4 protein expression and the increased LINC00618 expression, GSH levels, GPX4, SLC7A11, and FSP1 protein expression. In conclusion, LF high dose was the most renoprotective against GNT-induced AKI, in which suppression of ferroptosis pathways was a likely contributor to its protective mechanism. [Display omitted] •Ferroptosis is involved in gentamicin (GNT)-induced acute kidney injury (AKI).•Lactoferrin (LF) treatment mitigated GNT-induced AKI in a dose-dependent manner.•LF can be renoprotective via inhibition of ACSL4/TFR1/NCOA4 ferroptosis pathways.•LF via enhancement of SLC7A11, GPX, and FSP1 can inhibit ferroptosis.•LF lessened the expression of miR-378a-3p and LINC00618 involved in ferroptosis.