Kidney Week

Abstract: FR-PO0325

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

Session Information

• Diabetic Kidney Disease: Basic and Translational Science Advances - 1
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Hong, Yu Ah, Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Yu Ah Hong, MD, PhD

• Yang, Keum-Jin, Clinical Research Institute, Daejeon St. Mary’s Hospital, Daejeon, Korea (the Republic of)

Keum-Jin Yang, PhD

• Lee, Sun Ha, Clinical Research Institute, Daejeon St. Mary’s Hospital, Daejeon, Korea (the Republic of)

Sun Ha Lee

• Kim, Sungmi, Division of Nephrology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Sungmi Kim, MD

• Youn, Sojung, Division of Nephrology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Sojung Youn, DrMed

• Park, Hwajin, Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Hwajin Park, MD

• Hwang, Yunkyeong, Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Yunkyeong Hwang, MD

• Han, Suyeon, Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Suyeon Han, MD

• Chang, Yoon-Kyung, Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Yoon-Kyung Chang, MD, PhD

• Park, Cheol Whee, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (the Republic of)

Cheol Whee Park, MD

Background

Lipotoxicity plays a key role in the pathophysiology of diabetic kidney disease (DKD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) a major regulator of LDL receptor degradation, is a potential therapeutic target for hyperlipidemia. We investigated whether PCSK9 inhibition attenuates DKD by reducing lipotoxicity through AMP-activated protein kinase (AMPK) activation.

Methods

Male C57BLKS/J db/m and db/db mice at 8 weeks of age were divided into four groups: db/m control, db/m with PCSK9 inhibitor, db/db control, and db/db with PCSK9 inhibitor. SBC-115076, a PCSK9 inhibitor (1.5 mg/kg), was administered daily via subcutaneous injection for 8 weeks. HK-2 cells exposed to high glucose (HG) conditions were also treated with SBC-115076 for 48 hours to assess AMPK signaling and related pathways.

Results

PCSK9 inhibitor significantly reduced urine albumin-to-creatinine ratio, improved histologic changes in db/db mice. It also lowered LDL-cholesterol, triglyceride, and free fatty acid levels in both serum and kidney tissue. PCSK9 was predominantly expressed in proximal tubules and suppressed by PCSK9 inhibitor. PCSK9 inhibition increased LDL receptor and decreased CD36, enhanced AMPK phosphorylation, and activated PGC-1α. These effects were associated with suppression of SREBP-1c, upregulation of CPT1, and decreased phosphorylation of ACC. Furthermore, PCSK9 inhibition reduced phosphorylation of Akt and FoxO3a, leading to an increased BCL-2/BAX ratio. Markers of oxidative stress and apoptosis, such as 8-OHdG, TUNEL staining, and malondialdehyde levels, were also reduced by PCSK9 inhibitor.
In HG-treated HK-2 cells, PCSK9 inhibition enhanced AMPK phosphorylation, upregulated PGC-1α and CPT1, suppressed SREBP-1c, and decreased phosphorylation of ACC and FoxO3a. Importantly, knockdown of AMPK reversed these effects, suppressing PGC-1α, increasing SREBP-1c and phosphorylated ACC, and exacerbating lipid peroxidation and oxidative stress despite PCSK9 inhibitor treatment.

Conclusion

PCSK9 inhibition reduces renal lipotoxicity in diabetic kidney disease by activating AMPK, which suppresses lipogenesis, enhances fatty acid oxidation, and lowers oxidative stress and apoptosis. This suggests PCSK9 inhibition as a potential therapy for diabetic kidney disease.

Funding

• Government Support – Non-U.S.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20256pybbkcw