Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity

Abstract

Obesity increases plasma renin activity and angiotensin II levels, leading to vascular damage, elevated blood pressure, diabetes mellitus, and renal damage. Because genetic deletion of crucial parts of the renin-angiotensin system protect against obesity-related cardiovascular defects, we hypothesized that Dahl salt-sensitive (SS) rats, a model of chronically low plasma renin activity and angiotensin II levels, would be protected against vascular defects during diet-induced obesity compared with SS.13(BN) consomic rats showing normal renin-angiotensin system regulation. We evaluated vascular function in middle cerebral arteries of SS or SS.13(BN) rats fed high-fat (45% kcal from fat) versus normal-fat diet for 15 to 20 weeks from weaning. Endothelium-dependent relaxation in response to acetylcholine (10(-8) to 10(-4) mol/L) was restored in middle cerebral arteries of high-fat SS rats versus normal-fat diet controls, whereas vasodilation to acetylcholine was dramatically reduced in high-fat SS 13(BN) rats versus normal-fat diet controls. These findings support the hypothesis that physiological levels of angiotensin II play an important role in maintaining normal vascular relaxation in cerebral arteries and suggest that the cerebral vasculature of the SS rat model is genetically protected against endothelial dysfunction in diet-induced obesity.

Figure 1

Body weight progression and food intake of SS-13^BN vs. SS rats fed high fat (HF) or normal fat diet (NFD) diet. Comparison of increase in body weights over the course of treatment with either high fat (HF) or normal fat (NFD) diet (A) and food intake in g/day (B). * P < 0.05 SS HF vs. NFD control. ^# P < 0.05 vs. SS-13^BN on same diet. Data are expressed as mean ± SEM for n≥ 8.

Figure 2

Chronic mean arterial blood pressure measured in conscious animals. SS HF rats show significant increase in chronic MAP. *P<0.05 vs. NFD control. ^# P < 0.05 vs. SS-13^BN on same diet (n≥6 per group).

Figure 3

Response to acetylcholine (ACh) (A) and DETA-NONOate (B) in cannulated MCA of SS and SS.13^BN rats fed NFD or HF diet. Data expressed as mean ± SEM for n ≥ 6. * P < 0.05 SS HF diet vs. SS NFD; $ P < 0.05 SS13^BN HF diet vs. SS13^BN NFD; #-P < 0.05 SS NFD vs. SS13^BN NFD; &- P < 0.05 SS HF diet vs. SS-13^BN HF diet.

Figure 4

Effect of tempol (A, B) or losartan (C, D) on response of cannulated MCA to acetylcholine (ACh) in SS and SS.13^BN rats fed NFD (A, C) or HF diet (B,D). Untreated control responses were compared in Figure 3. Data are expressed as mean ± SEM for n ≥ 6, except for SS.13^BN + tempol (n=2) on NFD. * P<0.05 SS control vs. SS treated (tempol or losartan); $ P < 0.05 SS13^BN control vs. SS.13^BN treated (HF tempol, losartan NFD and HF diet); # P<0.05. SS treated vs. SS.13^BN treated. Due to the small N, no statistical comparisons were made with SS.13^BN + tempol. Previous studies (Reference 19) have shown that ACh-induced dilation in MCA of SS.13^BN on NFD is unaffected by tempol.

Figure 5

Effect of high fat (HF) diet vs. normal fat diet (NFD) on microalbumin (A), urinary protein (B), and protein casts in renal tubules (C) of SS vs. SS-13^BN rats. Protein casts were quantified from. *P<0.05 vs. NFD control and # P<0.05 vs. SS.13^BN on same diet. (n≥8 per group).

Figure 6

Expression of CuZnSOD (A), MnSOD (B), eNOS (C), p-eNOS (D), angiotensin type 1 receptor (AT₁R) (E), and angiotensin type 2 receptor (AT₂R) (F) in cerebral arteries of SS and SS.13^BN rats fed high fat (HF) or normal fat diet (NFD). *P<0.05 vs. NF control and # P<0.05 vs. SS.13^BN (n≥6 per group).