Nrf2 signaling attenuates epithelial-to-mesenchymal transition and renal interstitial fibrosis via PI3K/Akt signaling pathways

Background: Nrf2 constitutes a therapeutic reference point for renal fibrosis and chronic kidney diseases. Nrf2related signaling pathways are recognized to temper endothelial-to-mesenchymal transition (EMT) in fibrotic tissue. Nevertheless, the mechanism by which Nrf2 mitigates renal interstitial fibrosis is imprecise. Methods: The relationship between Nrf2 and renal interstitial fibrosis was investigated using the unilateral ureteral obstruction (UUO) model of Nrf2(-/-) mice. The mice were separated into four groups, based on the treatment and intervention: Nrf2(-/-) UUO, Nrf2(-/-) + Sham, WT + UUO and WT + Sham. Histological examination of renal tissue following the hematoxylin-eosin and Masson staining was carried out, as well as immunohistochemical staining. Additionally, to confirm the in vivo discoveries, in vitro experiments with HK-2 cells were also performed. Results: The Nrf2(-/-) UUO group showed more severe renal interstitial fibrosis compared to the WT + UUO, Nrf2(-/-) + Sham and WT + Sham groups. Furthermore, the manifestations of a-SMA and Fibronectin significantly increased, and the manifestation of E-cadherin considerably decreased in kidney tissues from the group of Nrf2(-/-) + UUO, compared to the WT + UUO group. The Nrf2 protein level significantly decreased in HK-2 cells, in reaction to the TGF-beta 1 concentration. In addition, the overexpression of Nrf2 presented contradictory results. What is more, the PI3K/Akt signaling pathway was discovered to be activated in the proteins extracted from cultured cells, and treated with Nrf2 siRNA and kidney tissues from the Nrf2(-/-) + UUO group. Conclusions: The results we obtained demonstrate that Nrf2 signaling pathway may perhaps offset the development of EMT, prompted by TGF-beta 1 and renal interstitial fibrosis. Likewise, the anti-fibrotic effect of Nrf2 was imparted by the inactivation of PI3K/Akt signaling. From our discoveries, we deliver new insight related to the prevention and treatment of kidney fibrosis.