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INTRARENAL ANGIOTENSINOGEN PRODUCTION INDUCED BY CHRONIC ANGIOTENSIN II AND HIGH SALT INTAKE IS AUGMENTED IN TUMOR NECROSIS FACTOR‐ALPHA RECEPTOR TYPE 1 KNOCKOUT MICE
Author(s) -
Mehaffey Eamonn P.,
Castillo Alexander,
Navar L. Gabriel,
Majid Dewan S. A.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1216.13
Subject(s) - endocrinology , medicine , angiotensin ii , receptor , chemistry , kidney , excretion , tumor necrosis factor alpha , renin–angiotensin system , urinary system , knockout mouse , blood pressure
Chronic angiotensin II (AngII) treatment increases TNF‐α generation in the kidney and also enhances intrarenal angiotensinogen (AGT) formation. However, the link between TNF‐α increase and AGT formation in the kidney remains unclear as it has also been demonstrated in‐vitro that TNF‐α suppresses AGT production in cultured human proximal tubule cells. These findings may indicate differential activation of TNF‐alpha receptors type 1 (TNFR1) and type 2 (TNFR2) signaling pathways induced by chronic AngII infusion. We examined the hypothesis that chronic elevation in AngII levels coupled with high salt (HS) intake reduces TNFR1 activity but enhances TNFR2 activity that induces cellular responses leading to increased formation of intrarenal AGT. We assessed the renal and systemic responses to chronic infusions with AngII (25 ng/min; implanted minipump) with high salt (HS; 4% NaCl) diets for 4 weeks in mice lacking TNFR1 receptors (TNFR1KO; n=7) and in mice lacking TNFR2 (TNFR2KO; n=6) and compared these responses to those in wild‐type (WT; C57BL6 strain, n=6) mice. Systemic blood pressure (SBP) was measured by tail‐cuff plethysmography and 24‐hour urine collections were done using metabolic cages at baseline and at 4 week periods. The urinary excretion rate of AGT (uAGT) was measured as a reflection of intrarenal generation of AGT using ELISA. Urinary excretion rates of sodium (U Na V) and potassium (U K V) were determined by analyzing urinary concentration of these electrolytes using flame photometry. The increase in mean SBP in response to AngII + HS for 4 weeks was greater in TNFR1KO mice (77±2 to 115±3 mmHg; P<0.05) compared to WT mice (76±1 to 102±2 mmHg; P<0.05), while the change in TNFR2KO (78±2 to 99±5 mmHg; P<0.05) had no difference from WT. Interestingly, the increase in uAGT after 4 weeks treatment period was also greater in TNFR1KO mice (6±2 to 167±75 ng/24hr; P<0.05) compared to WT mice (6±3 to 46±16 ng/24hr; P<0.05), while the changes in TNFR2KO mice (8±7 to 65±44 ng/24hr; P=0.11) were not significantly different from the changes in WT mice. All three groups showed similar increases in U Na V (WT, 118±13 to 883±121 mM/24hr; TNFR1KO, 96±15 to 942±86 mM/24hr; TNFR2KO, 94±8 to 733±195 mM/24hr) while no group experienced a significant change in U K V. The results suggest that TNFR1 activity mitigates the hypertensive response to chronic AngII infusion with high salt intake, likely by attenuating the increase in intrarenal AGT formation. Support or Funding Information Grant support: National Institute of General Medical Sciences IDeA Program (COBRE, P30GM103337) and Tulane Bridge Fund (DSAM).