The Intricate Interplay between Placental RAS Dysregulation, ADAM17, and IL-6 Highlights Key Mechanisms in Gestational Diabetes Mellitus
1
Biochemistry and Molecular Biology, University of dhaka, Dhaka, Bangladesh
Popul. Med. 2026;8(Supplement Supplement 1):A1223
ABSTRACT
BACKGROUND:
Gestational diabetes mellitus (GDM) is linked to deviations in placental structure, characterized by increased placental weight and thickness, heightened levels of oxidative stress, inflammation, and fibrosis. Placental renin angiotensin system (RAS) is crucial for placental development and successful pregnancy outcomes. In non-pregnant diabetes, it is reported that AT1R-driven inflammation and fibrosis occur. Angiotensin converting enzyme 2 (ACE2) guards against oxidative stress and ACE-AT1R-driven inflammation. ACE2 gene variants are also linked to GDM, FGR, and preeclampsia. ADAM 17 and interleukin-6 (IL-6) contribute to placental inflammation. Therefore, we hypothesize that in GDM, AT1R, ADAM 17, and IL-6 may rise, while ACE2 diminishes, potentially affecting placental health and thus might be responsible for the pathophysiology of GDM.
METHODS:
To investigate RAS components, placental tissue was collected from term pregnancies, including uncomplicated (n=40) and GDM cases (n=40). The expression of ACE, AT1R, ACE2, ADAM17, and IL-6 was quantified using qPCR.
RESULTS:
ACE and AT1R mRNA expression were higher in GDM compared to uncomplicated pregnancy. Whereas, there was a profound downregulation of ACE2 expression, largely due to increased shedding activity of ADAM17. This results in an elevated ACE/ACE-2 ratio, shifting the balance toward the vasoconstrictive and pro-inflammatory effects of angiotensin II, exacerbating oxidative stress, endothelial dysfunction, and placental vascular abnormalities. Additionally, ADAM17 positively correlates with IL-6, further promoting inflammation and metabolic disturbances. GDM pregnancies are also associated with increased placental weight, which correlates proportionally BMI and contributes to higher neonatal birth weight.
CONCLUSIONS:
The complicated relationship between placental RAS dysregulation, ADAM17 activity, and inflammatory pathways brings to light key mechanisms contributing to vascular and metabolic complications in GDM pregnancies. Deciphering these interactions is key to improving maternal–fetal outcomes.
Gestational diabetes mellitus (GDM) is linked to deviations in placental structure, characterized by increased placental weight and thickness, heightened levels of oxidative stress, inflammation, and fibrosis. Placental renin angiotensin system (RAS) is crucial for placental development and successful pregnancy outcomes. In non-pregnant diabetes, it is reported that AT1R-driven inflammation and fibrosis occur. Angiotensin converting enzyme 2 (ACE2) guards against oxidative stress and ACE-AT1R-driven inflammation. ACE2 gene variants are also linked to GDM, FGR, and preeclampsia. ADAM 17 and interleukin-6 (IL-6) contribute to placental inflammation. Therefore, we hypothesize that in GDM, AT1R, ADAM 17, and IL-6 may rise, while ACE2 diminishes, potentially affecting placental health and thus might be responsible for the pathophysiology of GDM.
METHODS:
To investigate RAS components, placental tissue was collected from term pregnancies, including uncomplicated (n=40) and GDM cases (n=40). The expression of ACE, AT1R, ACE2, ADAM17, and IL-6 was quantified using qPCR.
RESULTS:
ACE and AT1R mRNA expression were higher in GDM compared to uncomplicated pregnancy. Whereas, there was a profound downregulation of ACE2 expression, largely due to increased shedding activity of ADAM17. This results in an elevated ACE/ACE-2 ratio, shifting the balance toward the vasoconstrictive and pro-inflammatory effects of angiotensin II, exacerbating oxidative stress, endothelial dysfunction, and placental vascular abnormalities. Additionally, ADAM17 positively correlates with IL-6, further promoting inflammation and metabolic disturbances. GDM pregnancies are also associated with increased placental weight, which correlates proportionally BMI and contributes to higher neonatal birth weight.
CONCLUSIONS:
The complicated relationship between placental RAS dysregulation, ADAM17 activity, and inflammatory pathways brings to light key mechanisms contributing to vascular and metabolic complications in GDM pregnancies. Deciphering these interactions is key to improving maternal–fetal outcomes.
| eISSN: | 2654-1459 |
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