Angiotensin II-induced reduction in body mass is Ang II receptor mediated in association with elevated corticosterone

Abstract

The mechanisms by which elevated glucocorticoids contribute to decreased body mass via angiotensin II (Ang II) infusion are not completely described. This study addressed the hypothesis that chronic Ang II infusion suppresses hepatic growth hormone receptor (GHr) and IGF1 expressions via an Ang II receptor (AT1)-mediated pathway associated with elevated glucocorticoids. Sprague-Dawley rats were assigned to three groups: 1) Control, 2) Ang II-infused (80 ng/min x 28d) and 3) Ang II+angiotensin receptor blocker (ARB; 10 mg losartan/kg/d x 21d). After 28d, Ang II decreased body mass by 14% (407+/-8 vs 350+/-17 g) and hepatic AT1a, GHr, and IGF1 mRNA expressions by 45%, 44%, and 44%, respectively. ARB treatment completely prevented the loss in body mass (409+/-9 g) and AT1a and GHr expressions and partially recovered the loss of hepatic IGF1. Ang II increased plasma corticosterone (B) 3-fold (173+/-28 vs 555+/-42 ng/mL) and ARB treatment prevented the response (150+/-47 ng/mL). Food consumption did not change suggesting that the decrease in body mass resulted from the catabolic actions of the Ang II-induced increase in systemic B and not from reduced caloric intake. The prevention by ARB treatment of the Ang II-induced decrease in body mass and downregulation of AT1a, GHr and IGF1 coinciding with suppression of plasma B suggests that the Ang II-induced decrease in body mass is AT1 receptor mediated in conjunction with elevated B. These data suggest that alleviating the Ang II-induced cachexia requires targeting AT1 and suppressing glucocorticoid secretion.

Figure 1

Mean (± SE) body mass of A) Control and Angiotensin II (Ang II)-infused rats (n = 10/group) in Study 1, and B) Control (n = 8), Ang II (n = 7) and Ang II + angiotensin receptor blocker (ARB; n = 7) groups in Study 2. Ang II was infused (80 ng/min) for 28 d and ARB treatment (10 ng/kg/d in the diet) was initiated after the first week of Ang II infusion. * denotes significant (p < 0.05) difference from Control. Control and Ang II + ARB groups were not different.

Figure 2

Mean (± SE) relative organ masses from Control (n = 18), Angiotensin II (Ang II; n = 17), and Ang II + angiotensin receptor blocker (ARB; n = 7) groups. Ang II was infused (80 ng/min) for 28 d and ARB treatment (10 ng/kg/d in the diet) was initiated after the first week of Ang II infusion. * denotes significant (p < 0.05) difference from Control and # denotes significant (p < 0.05) difference from Angiotensin II. RP fat = retroperitoneal fat. Epi fat = epididymal fat pads.

Figure 3

Mean (± SE) relative units of mRNA expressions of hepatic angiotensin receptor type 1a (AT1a), growth hormone receptor (GHr), and insulin-like growth factor -1 (IGF1) from Control (n = 12), Angiotensin II (Ang II; n = 10), and Ang II + angiotensin receptor blocker (ARB; n = 6) groups. Ang II was infused (80 ng/min) for 28 d and ARB treatment (10 ng/kg/d in the diet) was initiated after the first week of Ang II infusion. * denotes significant (p < 0.05) difference from Control and # denotes significant (p < 0.05) difference from Angiotensin II.

Figure 4

Mean (± SE) A) plasma corticosterone (B) from Control (n = 17), Angiotensin II (Ang II; n = 14), and Ang II + angiotensin receptor blocker (ARB; n = 6) groups and B) urinary B excretion from Control (n = 10) and Angiotensin II (Ang II; n = 10) groups from Study 1. B) Insert: Mean (± SE) urinary B excretion from Control (n = 7), Angiotensin II (Ang II; n = 6), and Ang II + angiotensin receptor blocker (ARB; n = 6) groups on day 28 of Study 2. Ang II was infused (80 ng/min) for 28 d and ARB treatment (10 ng/kg/d in the diet) was initiated after the first week of Ang II infusion.. * denotes significant (p < 0.05) difference from Control and # denotes significant (p < 0.05) difference from Angiotensin II.

Figure 5

Correlation between the percent change in urinary corticosterone excretion and the percent change in body mass between Control and Angiotensin II (Ang II)-infused rats (n=10/group) for each day during Study 1. Ang II was infused (80 ng/min) for 28 d. The regression was considered significant at p < 0.05.