| Dendritic cell mineralocorticoid receptor controls blood pressure by regulating T helper 17 differentiation: role of the Plcβ1/4-Stat5-NF-κB pathway |
| 論文作者 |
Wang, YL; Zhu, H; Pan, YT; Shang, D; Du, LJ; Bai, L; Zhu, SW; Lin, WZ; Zhang, XY; Lu, HX; Bi, C; Liu, Y; Liu, Y; Xiao, H; Qian, YC; Zhou, B; Li, RG; Duan, SZ |
| 期刊/會議名稱 |
EUROPEAN HEART JOURNAL |
| 論文年度 |
2024 |
| 論文類別 |
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| 摘要 |
Background and Aims Dendritic cells (DCs) are closely related to blood pressure (BP) regulation. Mineralocorticoid receptor (MR) is an important drug target for antihypertensive treatment. However, the role of DC MR in the pathogenesis of hypertension has not been fully elucidated. This study aimed to determine the role of DC MR in BP regulation and to explore the mechanism. Methods Renal biopsy and peripheral blood samples were collected from hypertensive patients (HTN) for immunostaining and flow cytometry. Dendritic cell MR knockout (DCMRKO) mice, DC MR overexpressing (DCMROV) mice, DCMROV/IL-17A knockout (DCMROV/IL-17AKO) mice and finerenone-treated C57BL/6 mice were infused with angiotensin II (Ang II) to establish hypertensive models. Western blotting, chromatin immunoprecipitation, co-immunoprecipitation, and in vivo DC depletion or adoptive transfer were used to delineate the functional importance of DC MR in hypertension development. Results Mineralocorticoid receptor antagonists (spironolactone and finerenone) suppressed DC aggregation and activation, as well as hypertension in HTN and mice. Compared with littermate control (LC) mice, dendritic cell MR knockout mice had strikingly decreased BPs and attenuated target organ damage after Ang II infusion. Flow cytometry showed that DC MR deficiency mitigated Ang II-induced DC activation and T helper 17 (Th17) cell differentiation. RNA sequencing revealed that MR-deficient DCs had elevated expression of Plc beta 1 and Plc beta 4, knockdown of which reversed the inhibitory effect of MR deficiency on DC activation and Th17 differentiation. Adoptive transfer of MR-deficient DCs protected Ang II-induced hypertension, whereas knockdown of Plc beta 1/4 eliminated the protective effects. At the molecular level, MR negatively regulated Plc beta 1/4, which recruited SHP-1 to inactivate of Stat5 activity, resulting in enhanced NF-kappa B activation and Th17 polarization. Furthermore, DCMROV mice manifested more elevated BPs and target organ damage than control mice after Ang II infusion, and these differences were abolished in DCMROV/IL-17AKO mice. Finally, MR antagonists decreased the aggregation of Th17 in HTN and mice. Conclusions Dendritic cell MR plays important roles in the pathogenesis of hypertension by regulating Th17 through Plc beta 1/4-Stat5-NF-kappa B signalling, and blockade of DC MR is beneficial for treating hypertension. |
| 影響因子 |
37.6 |
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