Aims: Parietal epithelial cells (PECs) are potential stem cells within the glomerulus, migrating into site of podocyte loss to differentiate into podocytes. Little is known about the mechanism mediating differentiation of PECs into podocytes. Results: In vitro differentiation of PECs into podocytes led to upregulation of podocyte markers such as Wilms’ tumor gene 1 (WT-1), Forkhead box C1 (FOXC1), synaptopodin and podocin, accompanied by increased mitochondrial abundance. Preincubation with a mitochondrial reactive oxygen species (ROS) inhibitor prevented all these events in PECs. In vivo , adriamycin (ADR)-treated mice exhibited albuminuria, decreased WT1 positive cells, and claudin-1 expressed in glomerular capillary tuft, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) overproduction in PECs. Expression of the ROS-related molecule nuclear factor erythroid 2-related factor 2 (Nrf2) and its target protein Brahma-related gene 1 (Brg1) increased during differentiation of PECs into podocytes. Suppressing Nrf2 or Brg1 reduced the differentiation of PECs, whereas overexpression had the opposite effect. Brg1 directly regulated WT-1 transcription in PECs. Activation of Nrf2 with bardoxolone-methyl (CDDO-Me) resulted in less proteinuria and more WT1 positive cells in ADR mice. PECs conditional human Nrf2 knock-in mice showed increased WT1 cell numbers. Conclusion: It concluded that mitochondria-derived ROS mediated differentiation of PECs into podocytes via Nrf2 and Brg1 signaling. Antioxid. Redox Signal. 42, 393–407.

End-stage renal disease is a worldwide health burden, but the pathogenesis of uremia-associated cognitive impairment (CI) is poorly recognized. We hypothesized that uremia brings about deficiency of thiamin and folic acid and causes CI by inducing oxidative stress. Therefore, 24 Sprague-Dawley rats were randomly divided into two groups: a 5/6 nephrectomy group (n = 12) and a sham-operated group (n = 12). The Morris water maze was used to assess the cognitive function eight weeks post-surgery, and serum levels of thiamin, folic acid and homocysteine were detected subsequently. Brain and kidney tissues were collected for pathological examination and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) immunochemistry staining. Results showed that the escape latency on training days 1-2 was longer, and the time in quadrant IV on experimental day 6 was significantly shorter in 5/6 nephrectomy group. Meanwhile, the uremic rats showed decreased thiamin, folic acid and increased homocysteine. We also found the time in quadrant IV was positively correlated with thiamin and folic acid level, while negatively correlated with the blood urea nitrogen and 8-OHdG positive cell proportion. Furthermore, in 5/6 nephrectomy group, the hippocampal neuron count was significantly reduced, and a greater proportion of 8-OHdG positive cells were detected. Pretreating LPS-stimulated rat microglial cells with thiamin or folic acid in vitro alleviated the inflammatory impairment in terms of cell viability and oxidative stress. In summary, we applied a uremic rat model and proved that uremia causes serum thiamin and folic acid deficiency, homocysteine elevation, along with neuron reduction and severe oxidative stress in hippocampus, finally leading to CI.

Key Points: This trial evaluated the effects of henagliflozin on cardiac structure and its safety in patients with heart failure with preserved ejection fraction on dialysis. At week 24, henagliflozin achieved a statistically significant reduction in left ventricular mass index versus placebo (−5.27 g/m ² ; 95% confidence interval, −10.02 to −0.53 g/m ² ). Henagliflozin was tolerable in the peritoneal dialysis and hemodialysis settings. Background: Few effective drug treatments exist for patients with heart failure with preserved ejection fraction (HFpEF) on dialysis. The aim of this study was to evaluate the effects of henagliflozin, a sodium–glucose cotransporter 2 inhibitor, on cardiac structure and its safety in such population. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, patients with HFpEF on dialysis were randomly assigned (1:1) to receive henagliflozin or placebo for 24 weeks. All enrolled participants received conventional therapy. The primary outcome was change in left ventricular mass index (LVMI) from baseline to week 24. The secondary outcomes were changes in the left atrial volume index, E/e’, e’, and N -terminal pro-brain natriuretic peptide and safety. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. Analysis of covariance was used to assess treatment effects. Results: A total of 112 participants were randomly assigned to the henagliflozin group ( n =56) and placebo group ( n =56). Of these, 60 participants were on hemodialysis and 52 were on peritoneal dialysis. From baseline to week 24, henagliflozin resulted in a greater reduction in least-squares mean (±SEM) change in LVMI than placebo (−3.27±1.71 g/m ² versus 2.01±1.69 g/m ² ), with a between-group difference of −5.27 g/m ² (95% confidence interval [CI], −10.02 to −0.53 g/m ² ; P = 0.03). In the prespecified subgroup by dialysis modality, the between-group difference in LVMI change from baseline to week 24 was −6.86 g/m ² (95% CI, −14.02 to 0.29 g/m ² ) among participants on peritoneal dialysis and −3.91 g/m ² (95% CI, −10.45 to 2.63 g/m ² ) among participants on hemodialysis. No between-group differences in secondary outcomes were observed. The incidence of adverse events was similar between the henagliflozin and placebo groups (36% versus 34%). Conclusions: Henagliflozin was associated with a greater reduction in LVMI at week 24 compared with placebo and was tolerable in patients with HFpEF on dialysis. Larger studies are needed to confirm the LVMI-lowering effect of henagliflozin. Clinical Trial registry name and registration number: ChiCTR2300073169.