Mitochondrial dysfunction in proximal tubular epithelial cells is a key event in
acute kidney injury (AKI), which is a risk factor for the development of
chronic kidney disease (CKD).
Apelin is a bioactive
peptide that protects against AKI by alleviating
inflammation, inhibiting apoptosis, and preventing
lipid oxidation, but its role in protecting against mitochondrial damage remains unknown. Herein, we examined the protective effects of
apelin on mitochondria in
cisplatin-stimulated human renal proximal tubular epithelial cells and evaluated its therapeutic efficacy in
cisplatin-induced AKI mice. In vitro,
apelin inhibited the
cisplatin-induced mitochondrial fission factor (MFF) upregulation and the fusion-promoting
protein optic atrophy 1 (OPA1) downregulation.
Apelin co-treatment reversed the decreased levels of the deacetylase,
Sirt3, and the increased levels of
protein acetylation in mitochondria of
cisplatin-stimulated cells. Overall,
apelin improved the mitochondrial morphology and membrane potential in vitro. In the AKI model,
apelin administration significantly attenuated mitochondrial damage, as evidenced by longer mitochondrial profiles and increased
ATP levels in the renal cortex. Suppression of MFF expression, and maintenance of
Sirt3 and OPA1 expression in
apelin-treated AKI mice was also observed. Finally, exogenous administration of
apelin normalized the serum level of
creatinine and
urea nitrogen and the urine levels of NGAL and Kim-1. We also confirmed a regulatory pathway that drives mitochondrial homeostasis including PGC-1α, ERRα and
Sirt3. In conclusion, we demonstrated that
apelin ameliorates renal functions by protecting tubular mitochondria through
Sirt3 upregulation, which is a novel protective mechanism of
apelin in AKI. These results suggest that
apelin has potential renoprotective effects and may be an effective agent for AKI treatment to significantly retard CKD progression.