Prenatal Exposure to Lipopolysaccharide Alters Renal DNA Methyltransferase Expression in Rat Offspring

Area of Science:

• Developmental programming
• Epigenetics
• Cardiovascular research

Background:

• Prenatal exposure to inflammation is linked to adult hypertension, but underlying mechanisms remain unclear.
• Maternal inflammation, such as lipopolysaccharide (LPS) exposure, affects fetal cytokine levels (IL-6, TNF-α).
• Interleukin-6 (IL-6) is known to regulate DNA methyltransferases (DNMTs) via the transcription factor Fli-1.

Purpose of the Study:

• To investigate the role of intrarenal DNMTs in hypertension development following prenatal LPS exposure.
• To explore the molecular pathways involved in epigenetic alterations in offspring kidneys.

Main Methods:

• Pregnant rats were assigned to control, LPS, NF-κB inhibitor (PDTC), or LPS + PDTC groups.
• Offspring gene expression (IL-6, TNF-α, Fli-1, DNMT1, DNMT3B) and global DNA methylation levels in the renal cortex were analyzed.
• The impact of PDTC on LPS-induced changes was evaluated.

Main Results:

• LPS offspring exhibited significantly increased IL-6, Fli-1, TNF-α, DNMT1, and DNMT3B expression.
• Global DNA methylation in the renal cortex was markedly elevated in offspring from LPS-exposed mothers.
• Prenatal administration of PDTC normalized these increases in gene expression and DNA methylation.

Conclusions:

• Prenatal LPS exposure induces epigenetic changes in offspring kidneys, involving intrarenal DNMTs via the IL-6/Fli-1 and TNF-α pathways.
• These epigenetic modifications are implicated in the development of hypertension in offspring exposed to maternal inflammation.
• Inhibition of NF-κB signaling may offer a therapeutic strategy to prevent inflammation-induced developmental programming of hypertension.