Antenatal betamethasone exposure alters renal responses to angiotensin-(1-7) in uninephrectomized adult male sheep

Abstract

Antenatal corticosteroid exposure reduces renal function and alters the intrarenal renin-angiotensin system to favor angiotensin activation of angiotensin type 1 receptor (AT1R) mediated responses in ovine offspring. This study aimed to assess whether antenatal steroid exposure would affect renal responses to the direct intrarenal infusion of angiotensin-(1-7) in rams and the angiotensin receptors involved in mediating responses to the peptide. Adult, uninephrectomized rams exposed to either betamethasone or vehicle before birth received intrarenal angiotensin-(1-7) infusions (1 ng/kg/min) alone or in combination with antagonists to angiotensin receptors for 3 h. Basal sodium excretion (UNa) was significantly lower and mean arterial pressure was significantly higher in betamethasone- compared to the vehicle-treated sheep. Angiotensin-(1-7) decreased UNa more in betamethasone- than in vehicle-treated sheep. Candesartan reversed the response to angiotensin-(1-7) but D-Ala(7)-angiotensin-(1-7) did not. Angiotensin-(1-7) infusion decreased effective renal plasma flow in both groups to a similar extent and the response was reversed by candesartan, but was not blocked by D-Ala(7)-angiotensin-(1-7). Glomerular filtration rate increased significantly in both groups after 3 h infusion of angiotensin-(1-7) plus candesartan. These results suggest that antenatal exposure to a clinically relevant dose of betamethasone impairs renal function in rams. Moreover, angiotensin-(1-7) appears capable of activating the AT1R in uninephrectomized rams.

Keywords: Angiotensin-(1–7); antenatal betamethasone; programming hypertension; sodium excretion; unilateral nephrectomy.

Figure 1

Sodium excretion before and after 3 hours of intrarenal infusion of ANG – (1–7) alone, ANG-(1–7) with D-Ala, or candesartan in uninephrectomized vehicle- and betamethasone- treated sheep. # indicates a statistically significant difference between groups after infusion (P <0.05). A statistically significant difference within groups after infusion (*P <0.05 or ϕ P<0.01).

Figure 2

Changes in the fractional excretion (FENa) of sodium after 3 hours of intrarenal infusion of ANG-(1–7) alone, ANG-(1–7) with D-Ala, or candesartan in uninephrectomized vehicle-and betamethasone-treated sheep. (F=7.4, p<0.01 with treatment, Bonferroni post-test *p<0.05).

Figure 3

Effective renal plasma flow (ERPF) before and after 3 hours of intrarenal infusion of ANG-(1–7) alone, ANG-(1–7) with D-Ala, or candesartan in uninephrectomized vehicle- and betamethasone- treated sheep. A statistically significant difference within groups after infusion (*P <0.05 or ϕ P<0.01).

Figure 4

Glomerular filtration rate (GFR) before and after 3 hours of intrarenal infusion of ANG-(1–7) alone, ANG-(1–7) with D-Ala, or candesartan in uninephrectomized vehicle- and betamethasone- treated sheep. ^*indicates a statistically significant difference within groups after infusion (P <0.05).