Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

Abstract

Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

Tight junctions and acute kidney injury

“…In a rat model of cisplatin‐induced AKI, the expression of claudin‐2, occludin and ZO‐1 was notably decreased togheter with the disturbance in oxygen free radicals and inflammatory cytokines, while the expression of claudin‐5 remained unchanged (Lee et al, 2020; Trujillo et al, 2014). In the murine AKI model induced by folic acid, it was also observed that the expression of ZO‐1 was downregulated (Li et al, 2021b; Zhou et al, 2018). The change was associated with mitochondrial damage, resulting in excessive production of ROS and decreased ATP level, which further induced cell apoptosis and disruption of TJ structure.…”

“…Nephrotoxin‐induced AKI : In a murine model of folic acid‐induced AKI, FG‐4592 (Roxadustat) accelerated tubular repair by facilitating the recovery of tubular structural integrity and upregulating expression of ZO‐1 in TECs (Li et al, 2021b). FG‐4592 restored colonic epithelium TJ expression in CKD rats through the upregulation of miR‐223 induced by HIF‐1α (Qu et al, 2022).…”

Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications

“…Roxadustat protects against ischaemia/reperfusion-induced acute kidney injury through inhibiting the mitochondrial damage pathway in mice (Zhang M. et al, 2022). Roxadustat facilitates recovery from renal damage by ameliorating mitochondrial dysfunction induced by folic acid (Li X. et al, 2021). Roxadustat protects against renal ischemia/reperfusion injury by inhibiting inflammation (Miao et al, 2021).…”

Roxadustat: Not just for anemia

“… Huang et al (2020) showed that roxadustat inhibited experimental pulmonary fibrosis by regulating the TGF-β1/Smads signaling pathway in vitro and in vivo . Li et al (2021b) studied a folic acid (FA)-induced AKI model and found that roxadustat pretreatment promoted the regeneration of renal tubular structures 7 days after FA injection. They also found that roxadustat inhibited ferroptosis and inflammation due to activation of Nrf2 by Akt/GSK-3β, thereby inhibiting interstitial fibrosis ( Li et al, 2020b ).…”

“…Although current findings suggest the relationship of ROS and HIF is complex, and even differs in different cells and tissues, no clinical studies of roxadustat have reported elevated ROS levels. In fact, there is evidence that roxadustat reduced ROS production and attenuated FA-induced kidney damage ( Li et al, 2021b ). IRI is the most common cause of acute kidney injury.…”