Kisspeptin treatment improves fetal-placental development and blocks placental oxidative damage caused by maternal hypothyroidism in an experimental rat model

Abstract

Maternal hypothyroidism is associated with fetal growth restriction, placental dysfunction, and reduced kisspeptin/Kiss1R at the maternal-fetal interface. Kisspeptin affects trophoblastic migration and has antioxidant and immunomodulatory activities. This study aimed to evaluate the therapeutic potential of kisspeptin in the fetal-placental dysfunction of hypothyroid Wistar rats. Hypothyroidism was induced by daily administration of propylthiouracil. Kisspeptin-10 (Kp-10) treatment was performed every other day or daily beginning on day 8 of gestation. Feto-placental development, placental histomorphometry, and expression levels of growth factors (VEGF, PLGF, IGF1, IGF2, and GLUT1), hormonal (Dio2) and inflammatory mediators (TNFα, IL10, and IL6), markers of hypoxia (HIF1α) and oxidative damage (8-OHdG), antioxidant enzymes (SOD1, Cat, and GPx1), and endoplasmic reticulum stress mediators (ATF4, GRP78, and CHOP) were evaluated on day 18 of gestation. Daily treatment with Kp-10 increased free T3 and T4 levels and improved fetal weight. Both treatments reestablished the glycogen cell population in the junctional zone. Daily treatment with Kp-10 increased the gene expression levels of Plgf, Igf1, and Glut1 in the placenta of hypothyroid animals, in addition to blocking the increase in 8-OHdG and increasing protein and/or mRNA expression levels of SOD1, Cat, and GPx1. Daily treatment with Kp-10 did not alter the higher protein expression levels of VEGF, HIF1α, IL10, GRP78, and CHOP caused by hypothyroidism in the junctional zone compared to control, nor the lower expression of Dio2 caused by hypothyroidism. However, in the labyrinth zone, this treatment restored the expression of VEGF and IL10 and reduced the GRP78 and CHOP immunostaining. These findings demonstrate that daily treatment with Kp-10 improves fetal development and placental morphology in hypothyroid rats, blocks placental oxidative damage, and increases the expression of growth factors and antioxidant enzymes in the placenta.

Kisspeptin Suppresses Inflammasome-NLRP3 Activation and Pyroptosis Caused by Hypothyroidism at the Maternal-Fetal Interface of Rats

“…The activation of this pathway results from the activation of pattern recognition receptors (PRR), mainly toll-like receptors (TLRs), as well as cellular stress [ 37 , 38 ]. Therefore, we suggest that activation of this pathway in the animals of the present study may be associated with the increased placental expression of Tlr2 demonstrated in hypothyroid rats [ 12 ], as well as the oxidative stress, endoplasmic reticulum stress, and immune dysregulation observed in the maternal-fetal interfaces of these animals [ 12 , 15 , 33 ]. Although the activation of the inflammasome caused by hypothyroidism has been previously described in cardiac tissue, with increased protein expression of NLRP3 and Caspase 1 [ 44 ], this is the first study to describe inflammasome complex activation in decidual and placental dysfunction caused by maternal hypothyroidism.…”

“…This demonstrates the modulatory role of kisspeptin on the inflammasome-NLRP3-pyroptosis pathway for the first time. This effect of kisspeptin on this pathway may be the result of its antioxidant and immunomodulatory action [ 33 , 34 , 35 , 54 , 55 , 56 , 57 ], as already demonstrated with other inhibitors of the inflammasome-NLRP3 pathway [ 18 , 22 , 58 ].…”

“…Color deconvolution and thresholding were determined for each assessed region. Data from each region of the maternal-fetal interface were archived, analyzed, and expressed as staining area in pixels [ 12 , 32 , 33 ].…”

“…The primers for Nlrp3 , Il1β , Il18 , Caspase 1 , and Gasdermin D were designed based on the Rattus norvegicus mRNA sequence ( Table 1 ). Gene expression was calculated by the 2 −ΔΔCT method, where the results obtained for each group were compared quantitatively after normalization based on the expression of Polr2a Rattus norvegicus [ 12 , 33 , 69 ].…”

“…We recently demonstrated that maternal hypothyroidism also reduces the expression of kisspeptin and its receptor at the maternal-fetal interface of female rats [ 32 ] and that administration of kisspeptin improves fetoplacental development in these animals and suppresses oxidative stress [ 33 ]. Pharmacological inhibitors of the inflammasome pathway have broad therapeutic potential for the treatment of diseases that involve activation of this process [ 21 , 22 , 27 , 29 ].…”