Empagliflozin Prevents Cardiac Arrest-Induced Renal Injury Through BHB-Dependent Mitoribosome Maintenance
Abstract
Cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR) induces systemic ischemia and frequently results in acute kidney injury (AKI). The ketone body β-hydroxybutyrate (BHB) maintains mitochondrial and peroxisomal homeostasis through activation of the C/EBPβ-Pck1 axis, whereas Pck1 preserves mitoribosome integrity and mtDNA-encoded oxidative phosphorylation (OXPHOS) translation. However, it remains unclear whether this pathway is disrupted during CA/CPR-induced AKI and whether empagliflozin can restore its activity. Male C57BL/6J mice and proximal tubule-specific Pck1 conditional knockout (CKO) mice were subjected to short-duration or standard CA/CPR protocols. Empagliflozin was administered orally for 7 days before CA/CPR induction. Circulating BHB levels, renal expression of C/EBPβ and Pck1, and markers of mitochondrial, peroxisomal, and mitoribosomal abundance and function were evaluated using established methods. CA/CPR markedly reduced circulating BHB levels and suppressed the C/EBPβ-Pck1 signaling axis. These changes were accompanied by depletion of peroxisomal markers, mitochondrial regulators, and mitoribosomal components as well as increased tubular apoptosis and albuminuria. Pck1 CKO mice exhibited severe organelle dysfunction and aggravated renal injury. In contrast, empagliflozin restored BHB levels, preserved C/EBPβ and Pck1 expression, and maintained mitochondrial, peroxisomal, and mitoribosomal integrity, thereby attenuating tubular injury and…
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