Male Offspring Exposed to Maternal Hyperandrogenemia Have Exaggerated Pressor Response to Angiotensin II That Is Partially Attenuated by Etanercept
Authors: Agbo John , Quin Ruth , Reckelhoff Jane F. , Shawky Noha M. 
Published: May 2024

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy and major cause of hyperandrogenemia in women. Our group has previously shown that male offspring (F1) exposed to maternal hyperandrogenemia are born smaller (indicative of intra-uterine growth restriction) and have exaggerated pressor response to angiotensin (Ang) II as adults. Tumor necrosis factor-α (TNF-⍺) has been shown to play a role in Ang II-mediated hypertension in different models. Increased pressor response to Ang II could signal increased risk of cardiovascular diseases later in life. Therefore, the present study was designed to test the hypothesis that exposure to maternal hyperandrogenemia programs intrarenal inflammation that plays a role in the exaggerated pressor response to Ang II in male F1s. Methods: At 4 weeks (wks) of age, female Sprague Dawley (SD) rats were fed a purified diet (10% kcal from fat) and implanted (s.c.) with either 5α-dihydrotestosterone pellets (7.5 mg/90 d; hyperandrogenemic females (HAFs)) or placebo pellets (PBO), that were replaced throughout life. At 9-12 wks of age, HAFs and PBOs were paired with SD males and allowed to get pregnant, deliver and lactate their offspring (F1-HAF and F1-PBO) until weaning (3 wks of age). Urine was collected from male F1s (n = 6-10/grp, 4-5 months (mos) of age, 1 pup/litter) which were then euthanized. Kidney cortices were used for the assay of pro-inflammatory cytokines using Bioplex. Another batch of male F1s (n = 4-7/grp, 8-10 mos of age, 1 pup/litter) were implanted with radiotelemetry transmitters. After recovery, male F1s were treated with either etanercept (a TNF-⍺ antagonist; ETA; 1.2 mg/kg, twice a week s.c. injection; ETA-F1-HAF and ETA-F1-PBO grps) or vehicle (0.9% saline; VEH; VEH-F1-HAF and VEH-F1-PBO grps) for 2 wks. Mean arterial pressure (MAP) was then measured for 6 days (Pre-enalapril), followed by treatment with enalapril (25 mg/kg/d for 9 d in drinking water) then Enalapril + Ang II (150 ng/kg/min for 6 d, s.c. minipump). Results: Male F1-HAF had significantly higher renal cortical interleukin (IL)-1α, IL-1β, IL-7 and TNF-α (203.8 ± 14 vs 141.7 ± 10, 331.4 ± 27 vs 233.7 ± 13, 524.7 ± 41 vs 379.1 ± 46, and 579.8 ± 47 vs 423.7 ± 47 pg/g tissue, respectively; p<0.05 for all), proteinuria (14.1 ± 2.4 vs 8.6 ± 0.9 mg/24 h, p<0.05), urinary kidney injury molecule-1 (1058.0 ± 123 vs 557.0 ± 122 pg/24 h, p<0.05) compared to male F1-PBO. VEH-F1-HAF had exaggerated pressor response to Ang II compared to VEH-F1-PBO starting at day 3 until day 6 of Ang II (154 ± 6 vs 128 ± 6 mmHg, p<0.05) despite similar MAP pre-enalapril (116 ± 3 vs 118 ± 2 mmHg, p=NS) and after enalapril (97 ± 3 vs 96 ± 1 mmHg, p=NS). ETA-F1-HAF had significantly lower MAP compared to VEH-F1-HAF on days 3 (119 ± 10 vs 138 ± 3 mmHg, p<0.05), 4 (131 ± 9 vs 149 ± 5 mmHg, p<0.05) and 5 (142 ± 6 vs 154 ± 5 mmHg, p<0.05) of Ang II treatment. Yet, on day 6 of Ang II treatment, MAP was similar between VEH-F1-HAF and ETA-F1-HAF (154 ± 6 vs 146 ± 5 mmHg, p=NS) and significantly higher in both groups compared to ETA-F1-PBO (133 ± 12 mmHg) and VEH-F1-PBO (128 ± 6 mmHg) [p < 0.05]. Conclusion: Exaggerated pressor response to Ang II in male F1s exposed to maternal hyperandrogenemia could be partly mediated by the pro-inflammatory cytokine TNF-α. Future studies will determine the role of different immune cells in this response and the underlying epigenetic changes in male F1s exposed to maternal hyperandrogenemia. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM121334 (JFR, NMS), R01HL135089 (JFR), R01AG075963 (JFR). The content is solely the responsibility of the authors and does not necessarily represent the offcial views of the National Institutes of Health. This work was also supported by the American Heart Association Career Development Award Number 938320 (NMS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.