Table 1.
The Potential Role of Microglia in Hypertension
| Model of Hypertension | Treatment Details | Major Findings | Conclusion | References | |
|---|---|---|---|---|---|
| Animals | Protocol | ||||
| Male C57BL/6 and CD11b-DTR mice (8–10 weeks old) | Subcutaneous infusion of Ang II (1000 ng/kg/min) or oral administration of L-NAME (1.5 ng/mL in drinking water) for 4 weeks | DT ICV (1000 pg/g/d) to CD11b-DTR mice | The loss of microglia led to downregulated IL-1β and TNF-α expression in the CNS and decreased the levels of plasma vasopressin, kidney NE, and NMDA. | Microglia are the major cellular factors involved in neuroinflammation and BP regulation. | [32] |
| Male C57BL/6 mice (12–16 weeks old) | Implanted subcutaneously with a DOCA-silicone sheet (DOCA 1 mg/g body weight) and receiving 1% NaCl drinking water | 1. Kinin B1 receptor knockout; 2. R715, a specific B1R antagonist (70 µg/kg/day) |
1. DOCA administration upregulated the expression of Kinin B1R in the PVN and RVLM. 2. Kinin B1R deletion or blockade decreased BP, attenuated neuroinflammation and oxidative stress, and restored autonomic function. |
Kinin B1R blockade may represent a novel strategy to reduce neuro-inflammation, oxidative stress, and sympatho-excitation in neurogenic hypertension. | [47] |
| Male C57BL/6J mice (10 months old, 30–35 g) | 1. Infusion of Ang II (0.5 ng/kg/day in 9% NaCl) via an osmotic mini pump. 2. TREM2 overexpression in vitro |
None. | 1. Ang II induced hypertension exacerbated β-amyloid deposition and neuronal apoptosis, increased the number of activated microglia in the cortex and hippocampus of mice, and upregulated microglia TREM2. 2. TREM2 overexpression reversed M1 microglia-induced neuronal toxicity and decreased neuroinflammation. |
1. TREM2 plays an anti-neuroinflammatory role in microglia. 2. Controversy remains regarding whether TREM2 participates in the regulation of BP. |
[55] |
| Male C57BL/6 mice (25±5 g) | Electric foot shock with noises induced a stressed condition | RAGE knockout via Cre-CX3CR1/RAGEfl/fl mice | 1. Stress exposure increased the cytoplasmic translocation of HMGB1 in microglia. 2. Microglia-specific knockout of RAGE decreased M1 phenotypic polarization, MAP and sympathetic activities. |
Reducing neuroinflammation and SNS activity is associated with BP regulation | [57] |
| Male C57BL/6, CD11b-DTR and CX3CR1-GFP mice (8–10 weeks old) | ICV infusion of Ang II (500 ng/kg/min) | ICV infusion of a TGF-β neutralizing antibody (50 μg/day), recombinant TGF-β1 (50 ng/day), or DT (800 pg/g BW/day) | 1. Blockade of TGF-β signaling further increased BP in Ang II-treated mice. 2. The recombinant TGFβ1 treatment reversed the increased levels of MHC-II and TNF-α, reduced BP reduction, and upregulated the expression of pSMAD 2/3 and COX-2. |
Surveillant microglia are tightly regulated by TGFβ, which are critical for maintaining the homeostasis of the CNS and blood pressure. | [58] |
| Male Wistar–Kyoto rats and SHR rats (6 months old, 200–230 g) | Spontaneously hypertensive rats | Gavage of calcitriol (100 ng/kg) | Calcitriol treatment had no significant effect on BP regulation but it significantly decreased the number of Iba-1+ cells and levels of IL-1β and TNFα, and shifted microglia polarization from the M1 to M2 phenotype | VitD is neuroprotective in the hypertensive brain by modulating the brain ACE2/Ang(1–7)/MasR axis | [60] |
| Male Wistar-Kyoto rats and SHRs (7–8 weeks old, 175–225 g) | Spontaneously hypertensive rats | Intraperitoneal (i.p.) administration of the TLR4 antagonist TAK-242 (2 mg/kg/d) for 2 weeks | 1. TLR4 inhibition abolished microglia activation and preserved the BBB integrity in the PVN, RVLM, and NTS of SHRs. 2. TLR4 blockade attenuated the progression of MAP increases in SHRs and protected against autonomic dysfunction. |
TLR4 represents a viable alternative target in the treatment of hypertension. | [64] |
| Male Sprague–Dawley rats (250–280 g); Male SHRs, Wistar-Kyoto rats (6 weeks old) |
Subcutaneous infusion of Ang II (200 ng/kg/min). | ICV infusion of CMT-3 (3.5 µg/h) | 1. The ICV infusion of CMT-3 decreased the number of microglia and percentage of activated microglia. 2. Microglia inhibition also contributed to reduced expression of IL-1β, TNF-α, and TIMP-1, and decreased MAP. |
The link between microglia and certain microbial communities may have implications for the treatment of HTN. | [68] |
| SHRs and Wistar–Kyoto rats (12 weeks old) | Spontaneously hypertensive rats | Aerobic training for 5 days/wk, 1 h/day for 2 wks | Short-term aerobic training contributed to the decrease in HR, Iba-1+ cells, levels of pro-inflammatory cytokines, and the HMGB1 content and CXCR4 signaling in the PVN. | Aerobic training regulates microglia activation and the production of pro-inflammatory cytokines in the presence of hypertension | [72] |
Abbreviations: DTR, diphtheria toxin receptor; Ang II, angiotensin II; L-NAME, N(ω)-nitro-L-arginine methyl ester; DT, diphtheria toxin; ICV, intracerebroventricular injection; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor α; CNS, central nervous system; NE, norepinephrine; NMDA, N-methyl-D-aspartate; BP, blood pressure; RVLM, rostral ventrolateral medulla; SHRs, spontaneously hypertensive rats; CMT-3, chemically modified tetracycline-3; TIMP-1, tissue inhibitor of metalloproteinase-1; MAP, mean arterial pressure; HTN, hypertension; CVLM, caudal ventrolateral medulla; RA, renin-angiotensinogen transgenic; AGT, angiotensinogen; AAV, adeno-associated virus; eGFP, enhanced green fluorescent protein; AT1, Ang II type 1; AVP, arginine vasopressin; CX3CR1, C-X3-C motif chemokine receptor 1; sFKN, soluble fractalkine; NTS, nucleus tractus solitarii; IL-6, interleukin-6; DOCA, deoxycorticosterone acetate; TREM2, triggering receptor expressed on monocytes 2; RAGE, advanced glycation end product receptor; HMGB1, high-mobility group Box 1; SNS, sympathetic nervous system; TGF-β, transforming growth factor-β; MHC-II, major histocompatibility complex-II; pSMAD2/3, phosphorylated mothers against decapentaplegic 2/3; COX-2, cyclooxygenase-2; Iba1, ionized calcium-binding adapter molecule 1; VitD, vitamin D; ACE2, angiotensin I-converting enzyme 2; Ang (1–7), angiotensin (1–7); CXCR4, C-X-C chemokine receptor type 4; HR, heart rate; PVN, hypothalamic paraventricular nucleus.