Chronic Flutamide Treatment Alters Intrarenal Renin Angiotensin System Expression in Intrauterine Growth Restricted Female Rats

Intrauterine growth restriction (IUGR) programs an increase in blood pressure associated with early reproductive senescence in female IUGR rats at 12 months of age. Serum testosterone (T) levels are increased in female IUGR rats at this age mimicking the hormonal milieu of postmenopausal women (PMW). Testosterone is positively associated with blood pressure in PMW. Thus, our laboratory previously reported that chronic blockade of the androgen receptor with flutamide abolished hypertension in female IUGR rats. However, the mechanism remained unclear. Activation the renin angiotensin system (RAS) may be important in the etiology of hypertension in PMW. Therefore, for this study we tested the hypothesis that activation of the vasoconstrictor arm of the RAS would be attenuated via chronic blockade of the androgen receptor in female IUGR rats. Following a two week treatment with flutamide (8mg/kg/day) or vehicle, kidneys were harvested and separated into cortex and medulla. Cortical RNA was isolated then converted into cDNA. Real‐time PCR was performed using Bio‐Rad SYBR Green Supermix and iCycler using primers for renin, androgen receptor, angiotensin converting enzyme (ACE) and angiotensin converting enzyme 2 (ACE2). Levels of mRNA expression are reported for cycle threshold method. Intrarenal renin mRNA expression was increased 2.5 fold (2.6±0.65 vs. 1±0.42, P< 0.05) in renal cortex of IUGR vs. control kidneys. Following flutamide treatment, renin mRNA levels were normalized in IUGR vs. control (1.03±0.6 vs. 0.7±0.4). Androgen receptor and ACE expression were similar in vehicle control and IUGR rats; flutamide treatment had no further effect. There was a significant reduction in the ACE2 in vehicle treated IUGR relative to vehicle treated controls (0.84±0.12 vs. 1±0.11, P <0.05); however, flutamide treatment had no further effect on ACE2 expression. We previously reported that intrarenal ACE2 expression was increased in normotensive female IUGR offspring in young adulthood. Yet, we observe a reduction in intrarenal ACE2 expression with age in female IUGR rats. Thus, these data indicate that T may contribute to the etiology of hypertension in female IUGR rats via activation of the RAS. Since T causes activation of the RAS, targeting the androgen receptor could be a potential therapeutic intervention for postmenopausal hypertension. Support or Funding Information NIH: HL074927, HL51971, P20GM104357, AHA: GRNT19900004, 15PRE24700010