Collecting Duct NCOR1 Regulates Blood Pressure by Controlling Mineralocorticoid Receptor

Academic Background

Hypertension is one of the major risk factors for cardiovascular and cerebrovascular diseases globally, with complex and not fully elucidated mechanisms. The kidney plays a critical role in blood pressure regulation, particularly in the process of sodium ion reabsorption and excretion. The collecting duct, as the final segment of the renal tubule, can significantly impact overall sodium balance and blood pressure due to small changes in its sodium reabsorption function. In recent years, the role of Nuclear Receptor Corepressor 1 (NCOR1) in cardiovascular diseases has gradually gained attention, but its function in the kidney has not been thoroughly investigated.

This study aims to explore the role and mechanisms of collecting duct NCOR1 in blood pressure regulation, particularly its relationship with the Mineralocorticoid Receptor (MR) and the Epithelial Sodium Channel (ENaC). Through this research, the authors hope to provide new targets and strategies for the treatment of hypertension.

Source of the Paper

This paper was co-authored by Ke Sun, Yong-Li Wang, Chen-Chen Hou, and others, with affiliations including the Department of Nephrology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine; the Department of Nephrology at Huashan Hospital, Fudan University; and the Department of Cardiology at Shanghai Chest Hospital, Shanghai Jiao Tong University, among others. The paper was published in Journal of Advanced Research in 2025, with DOI: 10.1016/j.jare.2024.02.003.

Research Process and Results

1. Construction of Experimental Models

The study first constructed a collecting duct-specific NCOR1 knockout (KO) mouse model using gene editing technology. Specifically, floxed NCOR1 mice were crossed with mice expressing collecting duct-specific Cdh16-Cre recombinase to generate the KO mice. PCR and RT-qPCR confirmed the effective knockout of NCOR1 in the kidney.

2. Establishment of Hypertension Models and Blood Pressure Measurement

Two hypertension models were used to evaluate the impact of NCOR1 knockout on blood pressure:
- Angiotensin II (Ang II)-Induced Hypertension Model: Subcutaneous implantation of a mini-pump to continuously deliver Ang II (750 ng/kg/min) for 4 weeks.
- DOCA-Salt Hypertension Model: Induction of hypertension through deoxycorticosterone (DOCA) injections and a high-salt diet.

In both models, NCOR1 KO mice exhibited significantly higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared to control (LC) mice. Tail-cuff and telemetry methods further confirmed the negative effects of NCOR1 knockout on blood pressure.

3. Assessment of Vascular and Renal Injury

Histological analysis and RT-qPCR were used to study the effects of NCOR1 knockout on vascular and renal injury. Results showed significantly increased aortic wall thickening and fibrosis in KO mice, as well as elevated expression of renal fibrosis markers (e.g., Col1a1, α-SMA). Additionally, renal function was impaired in KO mice, evidenced by increased urinary albumin levels and oxidative stress markers.

4. Mechanisms of Sodium and Water Retention

The saline challenge test was conducted to assess sodium and water excretion in NCOR1 KO mice. Results indicated significantly reduced excretion of sodium and water in KO mice after Ang II infusion, suggesting exacerbated sodium and water retention. Further molecular studies revealed upregulated expression of ENaC subunits (Scnn1a, Scnn1b, Scnn1g) in the renal medulla of KO mice.

5. Interaction Mechanism Between NCOR1 and MR

To explore the molecular mechanism by which NCOR1 regulates ENaC, chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) experiments confirmed the interaction between NCOR1 and MR. Results showed that NCOR1 knockout increased MR enrichment on the promoters of ENaC genes, indicating that NCOR1 regulates ENaC expression by inhibiting MR transcriptional activity. Luciferase reporter assays further validated the inhibitory effect of NCOR1 on MR transcriptional activity.

6. Drug Intervention Experiments

To verify the roles of ENaC and MR in hypertension in NCOR1 KO mice, the study used the ENaC inhibitor amiloride and the MR antagonist spironolactone for intervention. Results showed that both amiloride and spironolactone significantly reduced blood pressure and improved vascular and renal injury in KO mice.

Conclusions and Significance

This study reveals that collecting duct NCOR1 interacts with MR to regulate ENaC expression, thereby influencing sodium reabsorption and blood pressure. NCOR1 knockout leads to increased MR transcriptional activity and upregulated ENaC expression, ultimately causing sodium and water retention and hypertension. This research not only uncovers the novel function of NCOR1 in the kidney but also provides a new potential target for hypertension treatment.

Research Highlights

1. Innovative Discovery: First to reveal the molecular mechanism by which collecting duct NCOR1 regulates ENaC expression through MR, thereby influencing blood pressure.
   
2. Model Construction: Successfully constructed a collecting duct-specific NCOR1 knockout mouse model, providing a reliable tool for further mechanistic studies.
   
3. Clinical Significance: The findings suggest that NCOR1 agonists or combination therapy with MR antagonists may become new strategies for hypertension treatment.
   

Other Important Information

This study was supported by the National Natural Science Foundation of China (81930120, 82330015, 81991503, 81921002) and the National Key Research and Development Program of China (2023YFA1801100).