High fat diet in female Dahl salt sensitive rats causes non‐neurogenic hypertension and minimal renal injury

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There is evidence in human subjects and animal models that obesity‐associated hypertension has a smaller neurogenic component in females than males. In addition, females typically show less severe hypertension, immune cell infiltration in the kidney and renal injury than males. The mechanistic links between these phenomena, however, are not clear. We previously found that feeding Dahl salt‐sensitive (SS) rats a high fat diet (HFD) from weaning through 6 months caused equivalent hypertension in male and female animals when compared to SS rats fed control diet (CD). Yet female rats exhibited significantly less renal injury than males. Therefore, in the current study, we quantified the contribution of neurogenic and other blood pressure control mechanisms to HFD associated hypertension in female Dahl SS rats. We also reexamined the impact of long‐term hypertension on histological indices of renal injury in these rats. After 24 weeks on diet feeding starting at weaning, all rats were hypertensive (via telemetric measurements), but HFD females (60% kcal from fat, 0.3% NaCl n=10) had significantly higher mean arterial pressure (MAP) than females fed the CD (10% kcal from fat, 0.3% NaCl, n=7) (MAP 165±4mmHg vs 141±3mmHg, p<0.05). Thereafter, all rats were treated sequentially with prazosin (150mg/L, 5days), atenolol (500mg/L, 7days), prazosin+atenolol (7days), trichlormethiazide (250mg/L, 5 days), and enalapril (250mg/L, 7 days) via the drinking water. Each treatment was followed by washout for 7 days. We found that MAP was moderately and similarly reduced by treatment with prazosin (−14±1mmHg vs −17±1mmHg), atenolol (−31±2mmHg vs −27±2mmHg), prazosin+atenolol (−26±1mmHg vs −29±2mmHg) and trichlormethiazide (−16±2mmHg vs −17±2mmHg) in CD versus HFD fed rats. Enalapril treatment caused more reduction of blood pressure than any other treatment, but the decreases of MAP were similar in CD and HFD fed rats (−36±5 mmHg vs −49±9 mmHg) (P>0.05). Renal histological alterations and immune cell infiltration were determined at 34–36 weeks on diet feeding. Overall CD and HFD fed rats showed similar, and low grade, renal injury scores and renal T‐cell (CD3+) and macrophage (CD68+) infiltration. However, a few HFD rats did show severe renal injury and inflammation, and we noted that in each of these animals MAP levels were consistently > 170 mmHg. Splenic immune cell analysis by flow‐cytometry did not support HFD associated alternations in immune cell population/distributions (CD4+, CD8+, NK cells, B cells et al). Taken together the data indicate that in the Dahl SS rats, HFD causes hypertension via mechanisms that do not include increased neurogenic support of blood pressure or volume expansion. Increased activity of the renin‐angiotensin system may play a part but is not wholly responsible. Female Dahl SS rats on HFD are strongly protected against hypertension‐associated renal inflammation and injury, but the mechanisms responsible remain unknown.Support or Funding InformationNHLBI 2P01HL070687 for G.D.F, J.J.G. and H.X