Obesity is a major risk factor for the development of hypertension and it is associated with hyperglycemia, hyperinsulinemia (type II diabetes), sodium retention and oxidative stress. However, the mechanisms involved in obesity related development of hypertension are not clearly understood. Development of hypertension can be explained in part by sodium retention resulting from impaired regulation of sodium homeostasis. Renal dopamine, acting via the renal dopamine D1 receptor (D1R), promotes the excretion of sodium and plays a vital role in the maintenance of sodium homeostasis.
Impairment of D1R function is associated with hypertension in humans and animal models including Leprfa/fa Zucker (obese) rats. We have previously reported that treatment of these rats with antioxidants or insulin sensitizers reduced insulin levels and oxidative stress, restored D1R function and reduced blood pressure. Further, the redox sensitive transcription factor, nuclear factor κ B (NFκB) has been implicated in impairment of D1R function during oxidative stress.
We investigated the effect of exercise on insulin levels, oxidative stress, nuclear translocation of NFκB, blood pressure, albuminuria, and D1R function. The exercise protocol involved treadmill exercise from three weeks of age for eight weeks. Exercise reduced oxidative stress, nuclear translocation of NFκB and albuminuria. However, exercise did not reduce plasma insulin levels or blood pressure. Also, selective D1R agonist (SKF38393) mediated increases in GTPγS binding and sodium excretion were impaired in obese rats compared to lean rats and exercise did not restore this defect. We concluded that, although exercise is beneficial in reducing oxidative stress and renal injury, reducing insulin levels may be required to restore D1R function in obese rats. This hypothesis is supported by our findings that three-week-old Leprfa/fa Zucker (obese) rats do not display oxidative stress, increased nuclear translocation of NFκB, or elevated blood pressure. However, they display hyperinsulinemia and impaired inhibition of Na+/K+ ATPase in response to D1R agonist.
Caloric restriction has been shown to attenuate hyperinsulinemia in obese rats. We hypothesized that caloric restriction in obese rats, starting from an early age, will reduce insulin levels, restore D1R function, and reduce blood pressure. Caloric restriction in obese rats reduced insulin levels by ~50%. However, it did not reduce oxidative stress, did not restore D1R function, or reduce blood pressure.
Therefore, we conclude that both hyperinsulinemia and oxidative stress can independently impair renal dopamine D1 receptor function and contribute to the development of hypertension in obese rats. Simultaneously reducing both oxidative stress and hyperinsulinemia might be required to restore renal dopamine D1 receptor function and lower blood pressure.Pharmacological and Pharmaceutical Sciences, Department o
