Activation of angiotensin type 2 receptors prevents diabetic complications in female db/db mice by nitric oxide‐mediated mechanisms

SHEN, JUSTIN Z.Y.; STECKELINGS, ULRIKE M.; DOMINICI, FERNANDO P.; BERNSTEIN, ELLEN A.; BERNSTEIN, KENNETH E.; DOMINICI, FERNANDO P.; BERNSTEIN, ELLEN A.; BERNSTEIN, KENNETH E.; VEIRAS, LUCIANA C.; QUIROGA, DIEGO T.; GIANI, JORGE F.; VEIRAS, LUCIANA C.; QUIROGA, DIEGO T.; GIANI, JORGE F.; SHEN, JUSTIN Z.Y.; STECKELINGS, ULRIKE M.

BRITISH JOURNAL OF PHARMACOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2020

0007-1188

Background and purpose: The angiotensin type 2 receptor (AT2 R) plays a role in metabolism by opposing the actions triggered by the angiotensin type 1 receptor (AT1 R). Activation of AT2 R has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT2 R activation improves metabolism in diabetic mice.Experimental approach: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT2 R agonist compound 21 (C21, 0.3 mg Kg-1 day-1 , subcutaneous). To evaluate whether the effects of C21 depend on nitric oxide (NO) production, a subgroup of mice were treated with C21 plus a sub-pressor dose of the NO synthase inhibitor L-NAME (0.1 mg ml-1 , drinking water).Key results: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared to saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared to saline-treated db/db mice. Insulin signaling analysis showed increased phosphorylation of insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared to saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue, and reduced adipocyte size in inguinal fat. The beneficial effects of AT2 R activation were associated with increased eNOS phosphorylation, higher levels of nitric oxide metabolites, and were abolished by L-NAME.Conclusion and implications: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.