Zinc-alpha2-glycoprotein Modulates Blood Pressure by Regulating Renal Lipid Metabolism Reprogramming-Mediated Urinary Na+ Excretion in Hypertension

Cardiovascular System Nephrology Medicine
Zinc-alpha2-glycoprotein Hypertension Lipid metabolism reprogramming Urinary Na+ excretion Kidney

Research Background

Hypertension is one of the most common and serious health problems worldwide, with its high prevalence closely linked to an increased risk of cardiovascular diseases and stroke. Although the pathogenesis of hypertension is complex and involves multiple organs or systems (such as the kidneys, arteries, microcirculation, heart, and central nervous system), recent studies have found that adipokines play an important role in blood pressure regulation. Zinc-alpha2-glycoprotein (ZAG) is a multifunctional glycoprotein initially recognized as an adipokine, primarily secreted by adipocytes. However, ZAG is also expressed in other cells (e.g., epithelial cells) and is found in serum and other body fluids. Although the role of ZAG in metabolic disorders has been studied, its specific mechanisms in hypertension remain unclear.

This study aims to explore the role of ZAG in hypertension, particularly its mechanism of regulating renal lipid metabolism reprogramming to affect urinary sodium excretion and blood pressure. Through this research, the authors hope to provide new targets for the prevention and treatment of hypertension.

Source of the Paper

This paper was co-authored by Xiaoxin Zhou, Chunyan Deng, Lin Chen, Lifu Lei, Xiaoliang Wang, Shuo Zheng, Caiyu Chen, Chengfeng Du, Valérie B. Schini-Kerth, and Jian Yang. The authors are affiliated with multiple research institutions, including the Research Center for Metabolic and Cardiovascular Diseases at the Third Affiliated Hospital of Chongqing Medical University and the Biomedical Research Center of Strasbourg, among others. The paper was published online on September 10, 2024, in the journal Cardiovascular Research.

Research Process

1. Relationship Between Serum ZAG Levels and Hypertension

First, the researchers measured serum ZAG levels in hypertensive patients and healthy subjects. The results showed that serum ZAG levels were significantly lower in hypertensive patients and were positively correlated with morning urinary sodium excretion. This finding suggests that ZAG may play a role in hypertension by regulating urinary sodium excretion.

2. Establishment of Animal Models and Blood Pressure Monitoring

To further investigate the role of ZAG in hypertension, the researchers constructed AZGP1 gene knockout mice (AZGP1−/−) and measured their blood pressure using 24-hour ambulatory blood pressure monitoring and the tail-cuff method. The results showed that blood pressure was significantly elevated in AZGP1−/− mice, and urinary sodium excretion was impaired. This indicates that ZAG deficiency may lead to hypertension.

3. Exploration of Renal Lipid Metabolism Reprogramming Mechanisms

To explore the mechanism by which ZAG deficiency causes hypertension, the researchers conducted multi-omics analysis (proteomics and metabolomics) on the kidneys of AZGP1−/− mice. The results showed that AZGP1 knockout led to renal lipid metabolism reprogramming, particularly a decrease in the activity of CPT1, a key enzyme in fatty acid β-oxidation, and an increase in the levels of its inhibitor, malonyl-CoA. This suggests that ZAG deficiency may inhibit CPT1 activity, leading to fatty acid accumulation, which in turn affects urinary sodium excretion and blood pressure.

4. Kidney-Specific ZAG Rescue Experiment

To validate the role of ZAG in the kidney, the researchers conducted a kidney-specific ZAG rescue experiment using adeno-associated virus (AAV9) to re-express ZAG in the renal tubules of AZGP1−/− mice. The results showed that ZAG rescue significantly reduced blood pressure and restored urinary sodium excretion in the mice. This further confirms the critical role of ZAG in the kidney.

5. Effect of NHE Inhibitor

To investigate the specific mechanism by which ZAG deficiency impairs urinary sodium excretion, the researchers used the NHE (Na+/H+ exchanger) inhibitor EIPA. The results showed that EIPA treatment reversed the impaired urinary sodium excretion in AZGP1−/− mice but had no effect on wild-type mice. This indicates that ZAG deficiency may affect urinary sodium excretion by increasing NHE activity.

6. Effect of Exogenous ZAG Protein

Finally, the researchers exogenously injected recombinant ZAG protein into spontaneously hypertensive rats (SHRs). The results showed that ZAG protein significantly reduced blood pressure and improved urinary sodium excretion in SHRs. This further supports the potential application of ZAG in hypertension treatment.

Research Results

The main findings of this study include: 1. Serum ZAG levels were significantly lower in hypertensive patients and SHRs and were positively correlated with urinary sodium excretion. 2. AZGP1−/− mice exhibited elevated blood pressure and impaired urinary sodium excretion. 3. AZGP1 knockout led to renal lipid metabolism reprogramming, particularly decreased CPT1 activity and increased malonyl-CoA levels. 4. Kidney-specific ZAG rescue experiments restored blood pressure and urinary sodium excretion in AZGP1−/− mice. 5. The NHE inhibitor EIPA reversed the impaired urinary sodium excretion in AZGP1−/− mice. 6. Exogenous ZAG protein significantly reduced blood pressure and improved urinary sodium excretion in SHRs.

Research Conclusion

This study found that ZAG deficiency increases the malonyl-CoA-mediated inhibition of CPT1 activity, leading to renal lipid metabolism reprogramming, which in turn causes fatty acid accumulation and increased NHE activity, ultimately resulting in decreased urinary sodium excretion and hypertension. This research reveals the important role of ZAG in hypertension and provides new potential targets for the prevention and treatment of hypertension.

Research Highlights

  1. Key Finding: This study is the first to reveal the mechanism by which ZAG affects urinary sodium excretion and blood pressure through the regulation of renal lipid metabolism reprogramming.
  2. Innovation: Through multi-omics analysis and kidney-specific rescue experiments, the study deeply explored the mechanism of ZAG in hypertension.
  3. Application Value: The research results provide new potential targets for the prevention and treatment of hypertension, particularly kidney-targeted therapeutic strategies based on ZAG.

Research Significance

This study not only reveals the important role of ZAG in hypertension but also provides new insights for the prevention and treatment of hypertension. By regulating ZAG expression or activity, more effective treatment options may be provided for hypertensive patients. Additionally, this study offers new perspectives for research on other metabolism-related diseases.