Key result
In mice lacking the tumor necrosis factor-alpha type 1 receptor, chronic Angiotensin II infusion with high salt intake resulted in a significantly greater increase in urinary angiotensinogen excretion (167 vs 46 ng/24 h) compared to wild-type mice.
Why the study?
In AngII and high-salt-induced hypertension, intrarenal AGT and TNF-alpha increase, but TNF-alpha suppresses tubular AGT formation, leading to the hypothesis that elevated AngII reduces renal TNFR1 activity to facilitate AGT formation.
Does TNFR1 deficiency exacerbate AngII and high salt-induced hypertension and intrarenal AGT formation in mice?
Does TNFR1 deficiency exacerbate AngII and high salt-induced hypertension and intrarenal AGT formation in mice?
Absolute Event Rate: 167% vs 46%
p-value: p=<0.05
TNFR1 plays a protective role against hypertension and intrarenal angiotensinogen formation induced by elevated AngII and high salt intake in mice.
In hypertension induced by angiotensin II (AngII) administration with high salt (HS) intake, intrarenal angiotensinogen (AGT) and tumor necrosis factor-alpha (TNF-α) levels increase. However, TNF-α has been shown to suppress AGT formation in cultured renal proximal tubular cells. We examined the hypothesis that elevated AngII levels during HS intake reduces TNF-α receptor type 1 (TNFR1) activity in the kidneys, thus facilitating increased intrarenal AGT formation. The responses to HS diet (4% NaCl) with chronic infusion of AngII (25 ng/min) via implanted minipump for 4 weeks were assessed in wild-type (WT) and knockout (KO) mice lacking TNFR1 or TNFR2 receptors. Blood pressure was measured by tail-cuff plethysmography, and 24-h urine samples were collected using metabolic cages prior to start (0 day) and at the end of 2nd and 4th week periods. The urinary excretion rate of AGT (uAGT; marker for intrarenal AGT) was measured using ELISA. HS +AngII treatment for 4 weeks increased mean arterial pressure (MAP) in all strains of mice. However, the increase in MAP in TNFR1KO (77 ± 2 to 115 ± 3 mmHg; n = 7) was significantly greater (p < 0.01) than in WT (76 ± 1 to 102 ± 2 mmHg; n = 7) or in TNFR2KO (78 ± 2 to 99 ± 5 mmHg; n = 6). The increase in uAGT at 4th week was also greater (p < 0.05) in TNFR1KO mice (6 ± 2 to 167 ± 75 ng/24 h) than that in WT (6 ± 3 to 46 ± 16 ng/24 h) or in TNFR2KO mice (8 ± 7 to 65 ± 44 ng/24 h). The results indicate that TNFR1 exerts a protective role by mitigating intrarenal AGT formation induced by elevated AngII and HS intake.
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Majid et al. (2021) studied Angiotensin II-induced hypertension with high salt intake (n=20). Angiotensin II + High salt diet in TNFR1 knockout mice vs. Wild-type mice was evaluated on Urinary angiotensinogen (uAGT) excretion rate at 4 weeks (p=<0.05). In mice lacking the tumor necrosis factor-alpha type 1 receptor, chronic Angiotensin II infusion with high salt intake resulted in a significantly greater increase in urinary angiotensinogen excretion (167 vs 46 ng/24 h) compared to wild-type mice.
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