Inhibition of Renin Angiotensin System Improves Leptin and Insulin Sensitivity, but Causes Severe Anemia Due to Hypothyroidism Public Deposited

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  • March 22, 2019
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  • Wang, Chih-Hong
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • An overactive Renin-Angiotensin System (RAS) is associated with the metabolic syndrome, and inhibiting RAS causes severe anemia. Our previous study has demonstrated that mice lacking renin (Ren1c) are lean and insulin sensitive. However, to our surprise the Ren1c-/- mice have low circulating total thyroid hormones, and their plasma catecholamine levels were similar to those of wild type (WT) mice. Although angiotensin II (Ang II) is suggested to regulate blood pressure, and insulin and glucose homeostasis, the precise mechanisms of its contribution to the metabolic syndrome are not completely understood. Obesity is often associated with leptin resistance, and leptin sensitivity is a potential therapeutic strategy to treat obesity. To establish the role of renin in the leptin sensitivity, and to investigate whether improved leptin sensitivity is responsible for lean and insulin sensitive phenotype of the Ren1c-/- mice, I generated mice lack of both renin and leptin (Ren1c-/-; ob/ob). The Ren1c-/-; ob/ob mice have lower body weight compared to the ob/ob mice at 3 months old despite similar food intake and fat weight to body weight ratio. They also have improved leptin sensitivity, demonstrated after leptin administration by larger decrease in body weight, body fat, and food intake in the Ren1c-/-; ob/ob mice relative to the ob/ob mice. In addition, the smaller body weight of Ren1c-/-; ob/ob mice are due to increased fecal fat excretion and fatty acid oxidation in the liver. Moreover, The Ren1c-/-;ob/ob mice are more insulin sensitive than the ob/ob mice as are the Ren1c-/- mice compared to wild type mice. Improved leptin and insulin sensitivity by the absence of renin was recapitulated by a type 1 Ang II receptor (AT1R) blocker losartan. Inhibiting AT1R improves leptin and insulin sensitivity, and may be useful in treating insulin resistance and leptin resistance in human obesity and diabetes. I next investigated whether the Ren1c-/- mice really have hypothyroidism, and if they have whether hypothyroidism contributes to anemia caused by inhibiting RAS. I provide evidence that the Ren1c-/- mice have tertiary hypothyroidism due to low expression of the hypothalamic TRH levels. Tertiary hypothyroidism of the Ren1c-/- mice causes impaired erythropoiesis in bone marrow and results in severe anemia, while exogenous thyroid hormone (T3) corrects it. Inhibition of AT1R or of Ang converting enzyme in WT mice recapitulated tertiary hypothyroidism and anemia in mice lacking renin. Although Ang II is suggested to stimulate erythropoiesis, my results demonstrated that hypothyroidism is the predominant cause of anemia induced by inhibiting RAS, and that without correcting hypothyroidism Ang II is not sufficient to correct anemia caused by RAS inhibition. Thyroid hormone is a potential therapeutic strategy for anemia of patients with chronic renal failure, who are treated with inhibitors for RAS.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology and Laboratory Medicine.
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  • Takahashi, Nobuyuki
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