BACKGROUND: Gentamicin (GM) is widely used as antibiotic but limited by its nephrotoxic effects. The kidney's proximal tubules, rich in mitochondria, rely on mitophagy to maintain mitochondrial integrity. However, impaired mitophagy contributes to mitochondrial dysfunction and accelerates acute kidney injury (AKI).
AIM: This study examined how FT, a long-acting β2-adrenergic receptor (β2-AR) agonist, can reduce GM-induced AKI and restore mitochondrial function by modulating the β2-AR-cAMP-CREB-PGC-1α-NRF1 axis and PINK1-Parkin-dependent mitophagy, as well as the related miR-421 and miR-103a.
METHODS: Forty male Swiss albino mice were divided into four groups: control, FT (0.1 mg/kg), GM (80 mg/kg, injected i.p. from days 8-14), and FT+GM (0.1 mg/kg FT injected for 14 days and 80 mg/kg GM injected from day 8 to 14). Renal function, histopathology, oxidative stress markers (malondialdehyde (MDA) levels, catalase (CAT) activity), ATP levels, cAMP, CREB, PGC-1α, NRF1 as β2-AR-downstream mediators, and mitophagy/autophagy-associated proteins and miR-421 and miR-103a were assessed.
RESULTS: FT markedly preserved renal histoarchitecture and ultrastructure observed by electron microscopy, improved renal function, and reduced tubular injury. It significantly decreased serum creatinine, blood urea nitrogen, albumin-to-creatinine ratio, and kidney injury molecule-1, while increasing urinary creatinine (p < 0.001) compared to GM group. FT enhanced CAT activity (p <0.01), reduced MDA (p < 0.001), and elevated ATP levels (p <0.01). Additionally, FT suppressed miR-421 and miR-103a (p < 0.01) gene expression and increased cAMP (p <0.01) concentration, CREB, PGC-1α, NRF1 (p <0.0001), PINK1, Parkin (p <0.05), LC3B (p <0.0001), and Beclin-1 (p <0.01) expressions, while downregulating p62 (p <0.0001) expression compared to GM group.
CONCLUSION: FT exhibited potent reno-protective effects against GM-induced AKI by restoring mitochondrial homeostasis via β2-AR-cAMP-CREB-PGC-1α-NRF1 axis and PINK1-Parkin-dependent mitophagy and related miR-421 and miR-103a.
