Chronic kidney disease (CKD) is well recognized as a distinct contributor to cardiac hypertrophy, while the underlying mechanism remains incompletely understood. Here, the authors show that myocardial mitochondrial oxidative damage is early and prominent in CKD and distinctively stimulates the STING-NFκB pathway by releasing mitochondrial DNA to drive cardiac hypertrophy. Furthermore, the authors reveal that ornithine decarboxylase (ODC1)-putrescine metabolic flux is transactivated by NFκB and is required for the STING-NFκB pathway to drive cardiac hypertrophy. Finally, genetic or pharmacologic inhibition of the myocardial mitochondria-STING-NFκB-ODC1 axis significantly prevents CKD-associated cardiac hypertrophy. Therefore, targeting the myocardial mitochoandria-STING-NFκB-ODC1 axis is a promising therapeutic strategy for cardiac hypertrophy in patients with CKD.
Keywords: ATP, adenosine triphosphate; CKD, chronic kidney disease; LV, left ventricular; MOMP, mitochondrial outer membrane permeabilization; MPTP, mitochondrial permeability transition pore; NRCM, primary neonatal rat cardiomyocyte; ODC1, ornithine decarboxylase; PUT, putrescine; ROS, reactive oxygen species; VDAC1, voltage-dependent anion channel 1; cGAS-STING pathway; cardiac hypertrophy; chronic kidney disease; mitochondria; mtDNA, mitochondrial DNA; polyamine metabolism; siRNA, small interfering RNA.
© 2022 The Authors.