Mechanisms of Diet-Induced Hypertension and Vascular Disease Risk in Dahl Rats

Abstract

Dahl salt-sensitive (SS) rats are genetically predisposed to cardiovascular-renal disease. These studies examined cardiovascular-renal outcomes in response to a high-fat diet/normal-salt diet in SS rats. In a separate study, we examined cardiovascular-renal disease risk in SS rats on different standard chow diet/normal-salt diets. We tested the hypotheses that: (1) a high-fat diet induces hypertension and renal injury in SS rats; (2) a high-fat diet enhances aortic vasoconstriction in SS rats; (3) a high-fat diet induces aortic perivascular adipose tissue (PVAT) dysfunction in SS rats; and (4) two standard chow diets, namely AIN-76A and Teklad diet, induce differential vasoconstriction or vasorelaxation phenotypes in aorta and small mesenteric arteries from SS rats. In the high-fat diet studies, rats were provided high-fat diet starting at 12 weeks old. At 16 weeks old, SS rats on the high-fat diet had hypertension and greater renal glomerular and tubular injury than SS-13BN rats. SS rats supplemented with the immunosuppressive drug mycophenolate mofetil (MMF; 30 mg/kg/day, oral) for the duration of the high-fat diet did not develop hypertension. High-fat diet was associated with reduced vasoconstrictive response to angiotensin II and increased acetylcholine-mediated vasorelaxation in SS rats via increased nitric oxide synthase (NOS) function in comparison to SS rats maintained on a normal-fat/normal-salt diet. In regards to PVAT function, high-fat diet increased thoracic aorta PVAT deposition and induced PVAT-mediated blunting of aortic vasoconstriction. In the standard chow diet studies, 16-week old SS rats placed on the AIN or Teklad diet at weaning had similar NOS functional regulation of vasoconstriction and vasorelaxation in large and small arteries. However, by using a diet-switch protocol, we demonstrated that SS rats placed on AIN diet at weaning and changed to Teklad diet at 12 weeks old had reduced NOS-mediated vasorelaxation and reduced NOS buffering of vasoconstriction in small arteries from SS rats, which was not observed in the corresponding diet-switch group. In conclusion, these studies highlight differential renal and vascular responses to a short-term high-fat diet, and even changes in standard chow diet, when genetically predisposed to hypertension.