L-kynurenine or nicotinamide supplementations mitigate uterine decidualization impairments during early pregnancy of uninephrectomized mice

Impaired renal reserve induced by unilateral nephrectomy (UNx) leads to the full-spectrum of phenotypes of preeclampsia (PE) in mice. L-kynurenine (a product of L-tryptophan metabolism) supplementation throughout the entire pregnancy rescues the PE-like phenotype in mice. However, whether UNx dams have endometrial decidualization deficiency during early pregnancy and whether L-kynurenine supplementation improve decidualization in UNx dams are not clear. While our prior study showed that nicotinamide (NAM) supplementation has beneficial effects on decidualization in mice with excess endothelin 1 (ET-1), whether NAM supplementation has a beneficial role in UNx dams is unknown. Here, we tested our hypothesis that UNx impairs uterine decidualization and L-kynurenine/MAM treatment improves decidualization. We compared implantation sites between sham dams, UNx dams, and UNx dams treated with L-kynurenine or NAM. Implantation sites of UNx dams had lagged embryos with distorted ectoplacental cone and reduced vascular density in mesometrial regions of deciduae. The decidual expression of VEGF-A and markers of decidualization (e.g., BMP2, prolactin) was decreased in UNx dams. Both L-kynurenine and NAM corrected the abnormality present in maternal-embryo interface of UNx dams. In addition, the decidual expression of ET-1 and its type B receptor decreased in UNx dams, and L-kynurenine/NAM increased their expression in the deciduae. Our results show that suppressed decidual ET-1/EDNRB signaling could play a role in the poor decidualization (decreased BMP2/prolactin) and angiogenesis (decreased VEGF) in UNx dams and both L-kynurenine and NAM have potential to improve embryo implantation and subsequent pregnancy outcomes.