Captopril Suppresses Polybrominated Diphenyl ether‐induced Pressor responses and Upregulation of RAAS gene markers Nr3c2 and Sgk1 Under Salt Loading in Rats

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Polybrominated Diphenyl Ethers (PBDEs) are organohalogens used as flame retardants in industries ranging from textiles to electronics, and are ubiquitous in our household environments. PBDEs are endocrine disrupting pollutants, and are toxic to the kidney and nervous system. We have previously shown that early life exposure to PBDEs permanently affects the cardiovascular system. In a previous report we demonstrated that perinatal exposure to PBDEs significantly exacerbates hyperosmotic‐induced pressor in adult rats. Follow up studies revealed that PBDE‐induced exaggerated blood pressure responses to stress are suppressed by the angiotensin converting enzyme (ACE) inhibitor and the mineralocorticoid receptor blocker, spironolactone, suggesting involvement of the Renin‐Angiotensin‐Aldosterone System (RAAS), including the kidney, in PBDE actions. Here we tested the hypothesis that developmental exposure to PBDEs enhance kidney RAAS processes in hyperresponsive rats. Dams were dosed perinatally from gestation day (GD) 4 to postnatal day (PND) 20 (except on day 0) with DE‐71, an industrial mixture of penta‐brominated and other PBDE congeners. At PND 60, baseline measures of systolic and mean arterial pressure and heart rate were recorded using non‐invasive blood pressure (NIBP) monitoring under isoflurane anesthesia (4% induction; 1.75% maintenance). Then, captopril was administered ad libitum via drinking water for two weeks. On the day of the experiment rats were hyperosmotically stimulated (3.5 M NaCl, 0.6ml/100 g b.w., i.p.) and 3 hours later NIBP measures recorded. Kidney gene expression was compared across hyperosmotically challenged and normosmotic rats that were exposed to PBDEs or oil vehicle (control), and treated with captopril or not. Using q‐PCR we examined gene markers for terminal RAAS effectors in the kidney and expressed as fold‐expression relative to the reference gene, b‐actin (Actb): mineralocorticoid receptor (Nr3c2); serum glucocorticoid kinase 1 (Sgk1), transcription of which is acutely regulated by Nr3c2 activation; and the Nr3c2 substrate regulator, hydroxysteroid 11‐betadehydrogenase 1 (Hsd11b1). A two‐way ANOVA revealed a significant main effect of captopril (p=0.00195) and PBDE (p=0.0423) on Nr3c2 gene expression. Post hoc comparisons revealed significant reductions in Nr3c2 fold expression between oil controls without and with captopril (p=0.0430; 1.024 ± 0.11 vs. 0.745 ± 0.099, n=4–5) and between PBDE exposed rats without and with captopril (p=0.0072; 1.252 ± 0.07 vs. 0.895 ± 0.101, n=5–6), indicating a novel mechanism of action of captopril on RAAS. We also demonstrate that relative to controls (n=5), PBDEs (n=6) significantly increased Sgk1 fold gene expression (p=0.042; 1.796 ± 0.432 vs. 1.082 ± 0.224, respectively), indicating a novel mechanism of action for PBDEs that may lead to acute salt‐induced hypertension via epithelial Na(+) channels (ENaC). Importantly, the PBDE upregulation of Sgk1 can be blocked by captopril. Support or Funding Information Supported by APS (J.L., D.P.), MARC (R.G.), and Sigma Xi Research Society (J.L.).