PCSK9 Inhibition Attenuates Renal Lipotoxicity by Activating AMPK in Diabetic Kidney Disease

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PCSK9 Inhibition Attenuates Renal Lipotoxicity by Activating AMPK in Diabetic Kidney Disease

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Co-author 1

Keum-Jin Yang nadia@cnu.ac.kr Daejeon St. Mary’s Hospital Clinical Research Institute Daejeon Korea (Republic of) -

Co-author 2

Soonha Lee oouing@daum.net Daejeon St. Mary’s Hospital Clinical Research Institute Daejeon Korea (Republic of) -

Co-author 3

Sungmi Kim rmb0979@hanmail.net Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) -

Co-author 4

Sojung Youn sjddestar@gmail.com Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) -

Co-author 5

Hwajin Park ghkwls1820@naver.com Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) -

Co-author 6

Yunkyung Hwang hyk125@naver.com Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) -

Co-author 7

Suyeon Han sooyaa1208@gmail.com Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) -

Co-author 8

Yoon-Kyung Chang racer@catholic.ac.kr Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) -

Co-author 9

Cheol Whee Park cheowhee@catholic.ac.kr Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) -

Co-author 10

Yu Ah Hong amorfati@catholic.ac.kr Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Department of Internal Medicine Seoul Korea (Republic of) *

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates the degradation of low-density lipoprotein (LDL) receptor, is a novel therapeutic target for hyperlipidemia. In this study, we determined whether PCSK9 inhibition attenuates diabetic kidney disease (DKD) by reducing lipotoxicity through the activation of AMP-activated protein kinase (AMPK).

Methods

Eight-week-old male C57BLKS/J db/m and db/db mice were divided into four groups. SBC-115076 (1.5 mg/kg) was administered daily via subcutaneous injection for 8 weeks. HK-2 cells exposed to high-glucose conditions were treated with SBC-115076 with or without AMPK siRNA for 48 h to assess the underlying AMPK-related molecular mechanism.

Results

PCSK9i significantly reduced albuminuria, improved renal histology, and decreased serum and renal levels of LDL-cholesterol, triglycerides, and free fatty acids in db/db mice. PCSK9 was predominantly expressed in proximal tubules and suppressed by PCSK9i. PCSK9 inhibition increased LDL receptor and decreased CD36 expression, enhanced AMPK phosphorylation, and activated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These effects were accompanied by the suppression of sterol regulatory element-binding protein 1c (SREBP-1c), upregulation of carnitine palmitoyltransferase 1 (CPT1), and reduced phosphorylation of acetyl-CoA carboxylase (ACC). Furthermore, phosphorylation of Akt, forkhead box O1 (FoxO1), and FoxO3a decreased, thereby mitigating oxidative stress and apoptosis. In high-glucose-treated HK-2 cells, PCSK9 inhibition enhanced AMPK phosphorylation, upregulated PGC-1α and CPT1, suppressed SREBP-1c, and decreased the phosphorylation of ACC and FoxO3a. Meanwhile, AMPK knockdown reversed these effects and exacerbated lipid peroxidation and oxidative stress, despite PCSK9i treatment.

Conclusion

PCSK9 inhibition ameliorates renal lipotoxicity in DKD by activating AMPK, which suppresses lipogenesis, enhances fatty acid oxidation, and reduces oxidative stress and apoptosis, suggesting its potential as a therapeutic strategy for DKD.

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