Br J Pharmacol. 2025 Jan 31. doi: 10.1111/bph.17440. Online ahead of print.
ABSTRACT
BACKGROUND AND PURPOSE: Kidney disease (KD) is a leading cause of mortality worldwide, affecting 〉10% of the global population. Two of the most common causes of KD are diabetes and acute kidney injury (AKI), both of which induce mitochondrial dysfunction resulting in renal proximal tubular damage/necrosis. Thus, pharmacological induction of mitochondrial biogenesis (MB) may provide a therapeutic strategy to block the onset/progression of KD. Here, we evaluated the pharmacological and potential therapeutic effects of a novel MB-inducing oxindole agent, MC16.
EXPERIMENTAL APPROACH: Primary cultures of rabbit renal proximal tubule cells (RPTCs) were used to evaluate the cellular signalling and MB-inducing effects of MC16. Mice were used to determine the MB-inducing effects of MC16 in vivo, and the metabolic effects of MC16 on the renal cortical metabolome. Mouse models of AKI and diabetic kidney disease (DKD) were used to demonstrate the therapeutic potential of MC16 to ameliorate acute and diabetic nephropathy.
KEY RESULTS: MC16 activated the PI3K-AKT-eNOS-FOXO1 axis and induced MB in RPTCs. MC16 induced MB and altered the renal cortical metabolome of mice. MC16 accelerated renal recovery, reduced vascular permeability, and diminished mitochondrial dysfunction following AKI. MC16 decreased diabetes-induced renal swelling, improved renal and mitochondrial function, and diminished interstitial fibrosis in DKD mouse models.
CONCLUSION AND IMPLICATIONS: MC16 is a novel compound that induces MB and ameliorates acute and diabetic nephropathy in mice. This study underscores that targeting MB following the onset of renal/metabolic insults may provide a therapeutic strategy to mitigate the onset and/or progression of KD.
PMID:39887970 | DOI:10.1111/bph.17440