*Article* **Involvement of Receptor for Advanced Glycation Endproducts in Hypertensive Disorders of Pregnancy**

**Juria Akasaka 1, Katsuhiko Naruse 1, Toshiyuki Sado 1, Tomoko Uchiyama 2, Mai Makino 2, Akiyo Yamauchi 2, Hiroyo Ota 2, Sumiyo Sakuramoto-Tsuchida 2, Asako Itaya-Hironaka 2, Shin Takasawa 2,\* and Hiroshi Kobayashi 1**


Received: 29 August 2019; Accepted: 28 October 2019; Published: 1 November 2019

**Abstract:** Preeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially life-threatening disease. Recently, PE/HDP has been considered to cause adipose tissue inflammation, but the detailed mechanism remains unknown. We exposed human primary cultured adipocytes with serum from PE/HDP and healthy controls for 24 h, and analyzed mRNA expression of several adipokines, cytokines, and ligands of the receptor for advanced glycation endproducts (RAGE). We found that the mRNA levels of interleukin-6 (*IL-6*), C-C motif chemokine ligand 2 (*CCL2*), high mobility group box 1 (*HMGB1*), and *RAGE* were significantly increased by the addition of PE/HDP serum. Among RAGE ligands, advanced glycation endproducts (AGE) and HMGB1 increased mRNA levels of *IL-6* and *CCL2* in SW872 human adipocytes and mouse 3T3-L1 cells. The introduction of small interfering RNA for *RAGE* (siRAGE) into SW872 cells abolished the AGE- and HMGB1-induced up-regulation of IL-6 and CCL2. In addition, lipopolysaccharide (LPS), a ligand of RAGE, increased the expression of IL-6 and CCL2 and siRAGE attenuated the LPS-induced expression of IL-6 and CCL2. These results strongly sugges<sup>t</sup> that the elevated AGE, HMGB1, and LPS in pregnan<sup>t</sup> women up-regulate the expression of IL-6 and CCL2 via the RAGE system, leading to systemic inflammation such as PE/HDP.

**Keywords:** hypertensive disorders of pregnancy; RAGE; AGE; adipocyte; IL-6; CCL2; LPS
