Decreased proportion of Foxp3+CD4+ regulatory T cells contributes to the development of hypertension in genetically hypertensive rats

Abstract

OBJECTIVE: Dysregulation of the sympathetic nervous system and the immune system has been highlighted in the pathogenesis of hypertension. Foxp3 regulatory T (Treg) cells, which maintain immune homeostasis, have potent antihypertensive properties. We systematically explored whether Treg cells proportions are altered in stroke-prone spontaneously hypertensive rats (SHRSP) with increased sympathetic activity. Then, we focused on Treg cells in the spleen and determined whether Treg cells proportion in the spleen could be affected by splenic sympathetic input associated with the progression of hypertension. We also investigated effects of Treg cell induction on hypertension development and cardiac hypertrophy in SHRSP. METHODS AND RESULTS: We evaluated Treg cells in SHRSP. Compared with normotensive Wistar-Kyoto (WKY) rats, SHRSP exhibited decreased proportions of CD4CD25Foxp3 cells (Treg cells) in the spleen before the onset of hypertension. Splenic sympathetic denervation in prehypertensive SHRSP attenuated the reduction of Treg cells at 4 weeks after denervation (P < 0.05) and delayed the development of hypertension in SHRSP. Interleukin (IL)-2 and anti-IL-2 mAb complex selectively induced Treg cells in vivo (P < 0.01), delayed the development of hypertension and decreased the heart weight/body weight ratio (4.64 ± 0.06 vs. 4.25 ± 0.05 mg/g, P < 0.01) and the cross-sectional area of cardiac myocytes in SHRSP compared with vehicle-treated SHRSP (580 ± 3.91 vs. 438 ± 4.43 μm, P < 0.0001). CONCLUSION: Our findings indicate that a decrease in Treg cell proportion is crucial for the development of hypertension and cardiac hypertrophy in SHRSP, which is involved in sympathetic neural input to the spleen.