PCSK9 Inhibition Attenuates Renal Oxidative Stress and Lipotoxicity in Diabetic Kidney Disease in Association with AMPK Activation

Renal lipotoxicity and oxidative stress are major contributors to diabetic kidney disease (DKD), but the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) and its relationship with AMP-activated protein kinase (AMPK) signaling remain unclear. We investigated the effects of PCSK9 inhibition on renal lipotoxicity and oxidative stress in db/db mice and high-glucose (HG)-treated HK-2 cells using a selective PCSK9 inhibitor (PCSK9i) with or without AMPKα1/α2 small interfering RNA (siRNA). PCSK9i significantly reduced albuminuria, renal injury, histopathological changes, and intrarenal lipid accumulation without altering glycemic control. These effects were accompanied by increased low-density lipoprotein receptor (LDLR) expression, reduced cluster of differentiation 36 (CD36) expression, enhanced AMPK phosphorylation and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) expression, reduced sterol regulatory element-binding protein-1c (SREBP-1c) expression, restored carnitine palmitoyltransferase 1 (CPT1) expression, modulated protein kinase B (Akt)/forkhead box O (FoxO) signaling, and reduced oxidative stress and apoptosis. Similar findings were observed in HG-treated HK-2 cells. Importantly, AMPK knockdown attenuated the protective effects of PCSK9i on lipid metabolism, oxidative stress, and apoptosis in HK-2 cells. PCSK9 inhibition attenuates renal lipotoxicity and oxidative stress in DKD, providing a preclinical rationale for further investigation of the renal metabolic effects of PCSK9-directed therapies and their association with AMPK activation.