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bioRxiv · 10.64898/2026.03.05.709322

Epigenetic Silencing of Carotid Body TRPM7 Attenuates Hypertension in Obese Mice

Shin, M. K.·Roy, A.·Paudel, O.·Gudapati, S.·Sham, J.·Tang, W.-Y.·Polotsky, V.
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Abstract

Obesity is the most common cause of hypertension. We have previously shown that high levels of circulating leptin in diet-induced obese (DIO) mice induced hypertension by increasing expression of Transient Receptor Potential Melastatin-subfamily member 7 (TRPM7) in the carotid bodies (CB). In addition, we demonstrated in rat PC12 cells that leptin increases Trpm7 gene expression by inducing CpG site-specific demethylation within the 5 regulatory region containing a signal transducer and activator of transcription 3 (STAT3) binding site. This leptin-induced Trpm7 upregulation was prevented by inhibition of JAK-STAT3 signaling. Based on these findings, we hypothesized that reversing region-specific methylation at the Trpm7 promoter in the CB could attenuate obesity-associated hypertension. Compared with lean controls, DIO mice exhibited increased Trpm7 expression and the STAT3- binding site-specific promoter demethylation in the CB. Administration of methylated DNA oligonucleotides targeting the STAT3 binding site attenuated CpG site-specific DNA demethylation and reduced Trpm7 transcription in the CB of DIO mice. This intervention resulted in decreased carotid sinus nerve activity and reduced arterial blood pressure, especially during the light phase. Our results suggest that targeted modulation of CpG site-specific DNA methylation at the Trpm7 promoter using DNA oligonucleotide may represent a novel therapeutic strategy for obesity-induced hypertension.

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Shin, M. K., Roy, A., Paudel, O., Gudapati, S., Sham, J., Tang, W.-Y., Polotsky, V.. 2026-03-07. Epigenetic Silencing of Carotid Body TRPM7 Attenuates Hypertension in Obese Mice. https://doi.org/10.64898/2026.03.05.709322

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