2. Academic Validation
  3. ANXA1 improves mitochondrial homeostasis through uncoupling protein 1 in diabetic nephropathy

ANXA1 improves mitochondrial homeostasis through uncoupling protein 1 in diabetic nephropathy

  • J Adv Res. 2025 Nov 22:S2090-1232(25)00935-X. doi: 10.1016/j.jare.2025.11.039.
Zi-Han Li 1,  Lu Fang 2,  Liang Wu 1,  Dong-Yuan Chang 1,  Manyuan Dong 2,  Liang Ji 2,  Qi Zhang 2,  Ming-Hui Zhao 3,  Sydney C W Tang 4,  Lemin Zheng 5,  Min Chen 6
Affiliations

Affiliations

  • 1 Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, China; Department of Nephrology, Peking University First Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, China.
  • 2 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China.
  • 3 Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, China; Department of Nephrology, Peking University First Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, China; Peking-Tsinghua Center for Life Sciences, Beijing 100034, China.
  • 4 Division of Nephrology, Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
  • 5 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China; Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Tiantan Xili, Chongwen District, Beijing 100050, China. Electronic address: zhengl@bjmu.edu.cn.
  • 6 Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, China; Department of Nephrology, Peking University First Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, China. Electronic address: chenmin74@sina.com.
PMID: 41275961 DOI: 10.1016/j.jare.2025.11.039
Abstract

Introduction: Diabetic nephropathy (DN) is a major public health concern. Our previous study found that annexin A1 (ANXA1) alleviated DN by improving mitochondrial homeostasis. However, the underlying mechanism is not fully clear yet.

Objectives: This study aimed to explore mechanisms by which ANXA1 improves mitochondrial homeostasis and identify novel therapeutic targets for DN.

Methods: Diabetic Anxa1-/-/uncoupling protein 1 (Ucp1)-/- mice and renal Ucp1/cardiolipin synthase 1 (Crls1)-overexpressing mice were constructed. Diabetes was established using high-fat diet (HFD) plus streptozotocin (STZ). CL316243 was used to upregulate UCP1 in db/db mice. Knockdown and overexpression in proximal tubular epithelial cells (PTECs) were constructed. Metabolomics and lipidomics were applied.

Results: Transcriptomics revealed that Ucp1 was the most significantly downregulated mitochondria-associated gene in kidneys of diabetic Anxa1-KO mice. Functional validation demonstrated that local overexpression of Ucp1 in kidneys alleviated urine albumin-to-creatine ratio (uACR), kidney injuries in histopathology and mitochondrial fission in Anxa1-KO diabetic mice. In vitro, UCP1 silencing abolished the improvements of human recombinant ANXA1 on high glucose (HG)-induced inflammation, fibrosis and mitochondrial dysfunction in PTECs. Silencing/overexpression of ANXA1 reduced/increased the stability of transcription factor GATA binding protein 3 (GATA3) in HK-2 cells under HG conditions, respectively. GATA3 could bind to the proximal promoter region of UCP1, thereby enhancing its transcriptional activity. UCP1 was significantly upregulated in kidneys of DN patients and mice. UCP1 deficiency reduced renal cardiolipin and exacerbated diabetes-induced kidney injury, including aggravated uACR, interstitial inflammation and fibrosis, and enhanced mitochondrial fission. Mechanistically, UCP1 upregulated CRLS1 by modulating aristaless-related homeobox (ARX), thereby promoting cardiolipin biosynthesis and reducing mitochondrial fission. Therapeutically, pharmacological upregulation of UCP1 by CL316243 attenuated established DN in db/db mice.

Conclusion: ANXA1 stabilized GATA3 to upregulate UCP1, which promoted cardiolipin biosynthesis through the ARX/CRLS1 axis, inhibited mitochondrial fission, thereby alleviated DN. This study highlighted the therapeutic potential of targeting UCP1 in DN.

Keywords

Annexin A1; Cardiolipin synthase 1; Diabetic nephropathy; GATA binding protein 3; Mitochondrial dynamics; Uncoupling protein 1.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z