Klotho Gene and Protein in Human Placentas According to Birth Weight and Gestational Age

Abstract

Introduction: Fetal growth restriction may be the consequence of maternal, fetal, or placental factors. The insulin-like growth factors (IGFs) are major determinants of fetal growth, and are expressed in the mother, fetus and placenta in most species. Previously we reported higher placental protein content of IGF-I, IGF-IR, and AKT in small (SGA) compared with those from appropriate for gestational age (AGA) placentas. The protein Klotho, has been reported in placenta and may regulate IGF-I activity. In this study we determined Klotho gene expression and protein immunostaining in term (T-SGA y T-AGA) and preterm (PT-SGA y PT-AGA) human placentas. In addition, we assessed the effect of Klotho on the IGF-IR and AKT activation induced by IGF-I.Methods: Placentas (n = 1 17) from 32 T-SGA (birth weight (BW) = −1.74 ± 0.08 SDS), 37 T-AGA (BW = 0.12 ± 0.12 SDS), 20 PT-SGA (BW = −2.08 ± 0.14 SDS), and 28 PT-AGA (BW = −0.43 ± 0.13 SDS) newborns were collected. mRNA expression by RT-PCR in the chorionic (CP) and basal (BP) plates of the placentas, and the presence of Klotho was evaluated by immunohistochemistry (integral optical density, IOD). In addition, we developed placental explants that were incubated with IGF-I in the presence or absence of Klotho.Results: We found a lower mRNA expression and protein immunoreactivity of Klotho in the CP of SGA (term and preterm) compared with AGA placentas. We also observed a significant reduction in IGF-IR tyrosine activation induced by IGF-I 10 nM when preincubated with 2.0 nM of Klotho (2.4 ± 0.5 arbitrary units vs. 1.3 ± 0.3 AU), and similar results we observed on AKT and ERK42/44 activation.Conclusion: We describe for the first time that Klotho mRNA and protein varies according to fetal growth and gestational age. In addition, Klotho appears to down-regulate the activation induced by IGF-I on IGF-IR and AKT, suggesting that Klotho may be regulating IGF-I activity in human placentas according to intrauterine fetal growth.

Advanced maternal age causes premature placental senescence and malformation via dysregulated α‐Klotho expression in trophoblasts

“…The results strongly suggested that AMA is an independent risk factor for the loss of placental α‐Klotho expression beginning in the early phase of pregnancy, implying that placental α‐Klotho expression is barely influenced by the life cycle of the placenta but is rather determined by maternal factors of the embryo. However, a previous study in another group showed that α‐Klotho expression in human placentas was downregulated as gestational age advanced (Iñiguez et al., 2018). The inconsistency between these findings may be due to the discrepancy in specimen collection.…”

“…The present study revealed that α‐Klotho is expressed in various types of trophoblasts in the human placenta, which is consistent with previous results (Fan et al., 2016; Loichinger et al., 2016), implying that α‐Klotho expression possesses critical biological and pathological relevance in the placenta. Indeed, it has been reported that α‐Klotho expression levels in placentas from women diagnosed with preeclampsia or who delivered offspring that were small for gestational age (SGA) are significantly lower than those in placentas from women with healthy pregnancies (Fan et al., 2016; Iñiguez et al., 2018). α‐Klotho plays a role in the activation of the IGF‐I signaling pathway, which is vital for fetal growth (Iñiguez et al., 2018; Ohata et al., 2011) and may be associated with maintaining the balance of the fetomaternal calcium gradient (Ohata et al., 2011).…”

“…Indeed, it has been reported that α‐Klotho expression levels in placentas from women diagnosed with preeclampsia or who delivered offspring that were small for gestational age (SGA) are significantly lower than those in placentas from women with healthy pregnancies (Fan et al., 2016; Iñiguez et al., 2018). α‐Klotho plays a role in the activation of the IGF‐I signaling pathway, which is vital for fetal growth (Iñiguez et al., 2018; Ohata et al., 2011) and may be associated with maintaining the balance of the fetomaternal calcium gradient (Ohata et al., 2011). Therefore, we speculated that these mechanisms may underlie the unfavorable birth outcomes associated with AMA.…”

Upregulation of Klotho Aggravates Insulin Resistance in Gestational Diabetes Mellitus Trophoblast Cells

“…Previous studies have shown that klotho induces down-regulation of the insulin/IGF signal [ 20 ]. In addition, klotho can down-regulate the activation of IGF-1 on IGF-1R and Akt [ 21 ].…”

Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants

“…Homozygous Klotho deficient mice have premature aging, spontaneous fibrosis, pulmonary emphysema and vascular dysfunction, while mice that over-express Klotho have extended life span and relative protection from cardiopulmonary injury 13 . Klotho is primarily expressed in the kidneys and choroid plexus 13 , but it is also present in the placenta 14 , lungs, parathyroid glands and heart 13 . Klotho exists in two main forms: full-length transmembrane Klotho and soluble Klotho, the latter being formed by proteolytic cleavage of membrane Klotho.…”