Sex Differences in Oxidative Stress Following Uniphrectomy in Antenatal Glucocorticoid Exposed Sheep

Abstract

Antenatal glucocorticoid (AG) administration is associated with nephron loss and sex specific reductions in renal function in adult offspring. It is not known if AG induced responses to a second renal insult also reflect sex differences.Therefore, we determined if AGs increase susceptibility of proximal tubule cells (PTC) to oxidative stress induced by a second hit, further nephron loss (uninephectomy UN) in a sex dependent fashion.1–1.5 year old rams and ewes exposed to either Betamethasone (BMX) (n=5) or Vehicle (V) (n=5) at 0.6 gestation underwent UN. Kidney cortex and proximal tubule cells (PTC) were obtained from one kidney at UN (1st kidney) and the other at necropsy two weeks later (2nd kidney). PTC were incubated with angiotensin II (Ang II) and the NADPH oxidase components (p47phox and NOX2) in cortex and 8‐isoprostane (8‐PGF) secretion in media were measured. ANOVA was used for data analysis.Antenatal BMX exposure or UN increased p47 expression in cortex in rams but not in ewes (F=23.1, p=0.003). Expression was higher in BMX exposed rams (F=6.5, P=0.02). NOX2 expression did not change. Ang II stimulated 8‐PGF secretion from PTC of the 1st and 2nd kidneys from BMX rams, but not ewes. The Ang II response was highest in PTCs from the 2nd kidney 139% (F=20.6, p<0.0001) and was blocked by candesartan, but enhanced by PD123319 (F=10.1, P=0.0004). We conclude that the kidneys in BMX exposed male sheep exhibit a greater susceptibility to a secondary insult than those of females. AT1 receptors contribute to Ang II induced oxidative stress, while AT2 receptors may attenuate the stress in PTC. The heightened response in males may reflect the increase in the NADPH oxidase components p47phox.. Supported by HD‐47584 and HD‐17644.