Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines.

Fibrosis occurs in many organs, and its sustained progress can lead to organ destruction and malfunction. Although numerous studies on organ fibrosis have been carried out, its underlying mechanism is largely unknown, and no ideal treatment is currently available. Ferroptosis is an iron-dependent process of programmed cell death that is characterized by lipid peroxidation. In the past decade, a growing body of evidence demonstrated the association between ferroptosis and fibrotic diseases, while targeting ferroptosis may serve as a potential therapeutic strategy. This review highlights recent advances in the crosstalk between ferroptosis and organ fibrosis, and discusses ferroptosis-targeted therapeutic approaches against fibrosis that are currently being explored.

Novel aspect of neprilysin in kidney fibrosis via ACSL4-mediated ferroptosis of tubular epithelial cells.

Although inhibition of neprilysin (NEP) might be a therapeutic strategy with the potential to improve the outcome of chronic kidney disease (CKD), the versatile function of NEP with its mechanism remains obscure in kidney fibrosis. In the study, we found that NEP was abnormally increased in tubular epithelial cells of CKD patients, as well as unilateral ureteral obstruction and adenine diet-induced mice. Treatment with a United States Food and Drug Administration-approved NEP inhibitor Sacubitrilat (LBQ657) could alleviate ferroptosis, tubular injury, and delay the progression of kidney fibrosis in experimental mice. Similarly, genetic knockdown of NEP also inhibited tubular injury and fibrosis in transforming growth factor (TGF)-ß1 -induced tubular cells. Mechanically, NEP overexpression aggravated the ferroptotic and fibrotic phenotype, which was restored by acyl-CoA synthetase long-chain family member 4 (ACSL4) knockdown. The NEP silencing attenuated TGF-ß1-induced tubular cell ferroptosis and was exacerbated by ACSL4 overexpression. Collectively, for the first time, a novel aspect of NEP was explored in kidney fibrosis through ACSL4-mediated tubular epithelial cell ferroptosis. Our data further confirmed that NEP inhibition exerted a promising therapeutic against fibrotic kidney diseases.

Additional antibiotic lock in peritoneal dialysis-associated refractory peritonitis: A case series study and literature survey.

BACKGROUND: Refractory peritonitis is one of the leading causes of catheter failure in peritoneal dialysis (PD) patients. However, there are no established curative therapies available, and only catheter removal should be performed. Here we present a case series study to illustrate the efficacy of antibiotic lock for PD-associated refractory peritonitis. MATERIALS AND METHODS: Patients with refractory peritonitis treated with intraperitoneal antibiotics plus antibiotic lock from September 2020 to March 2022 were retrospectively analyzed. Medical cure was identified as a success of treatment. RESULTS: We identified 11 patients, of which 7 (63.64%) had a history of PD-associated peritonitis, with the episode of continuous ambulatory peritoneal dialysis (CAPD) ranging from 1 to 158 months at a median of 36 (9.5, 50.5) months. The dialysis effluent culture showed Gram-positive, Gram-negative bacteria, and was culture-negative in 5, 2, and 4 cases, respectively. The cure rates were 85.71% for culture-positive cases and 25% for culture-negative cases, and the total cure rate was 63.64%. No relevant adverse events occurred, including sepsis. CONCLUSIONS: Treatment with the additional antibiotic lock was successful in most cases, especially in those that were culture-positive. Additional antibiotic lock deserves great attention and further investigation in treating PD-associated refractory peritonitis.

Fatty acid-binding protein 4 in kidney diseases: From mechanisms to clinics.

Considerable evidence indicated the relationship between fatty acid-binding protein 4 (FABP4) and kidney diseases. FABP4, a small molecular lipid chaperone, is identified to regulate fatty acid oxidation, inflammation, apoptosis, endoplasmic reticulum stress and macrophage-to-myofibroblast transition in kidney diseases. Many studies have shown that circulating FABP4 level is related to proteinuria, renal function decline, cardiovascular complications of end-stage renal disease and even the prognosis of kidney transplanted patients. Notably, pharmacological or genetic inhibition of FABP4 attenuated renal injury in the various experimental models of kidney diseases, making it promising to develop potential therapeutic strategies targeting FABP4 in kidney diseases. In this study, we updated and reviewed the mechanisms and clinical significance of FABP4 in kidney diseases.

Effects of Cyclosporine A on the Development of Metanephros in the Pregnant BALB/c Mice.

BACKGROUND:: Cyclosporine A (CsA) is a commonly used clinical immunosuppressant. However, CsA exposure in rabbits during the gestation period was shown to cause a postnatal decrease in the number of nephrons, with the effects remaining unknown. In this study, we aimed to explore the effects of CsA on metanephros development in the pregnant BALB/c mice. METHODS:: Pregnant mice were randomly divided into two groups, and CsA (10 mg·kg-1·d-1) was subcutaneously injected from gestation day 10.5 to day 16.5 in the CsA group, whereas a comparable volume of normal saline was given to the control group. All of the mice were sacrificed on gestation day 17.5 and serum CsA concentration was measured. The fetuses were removed and weighed, and their kidneys were prepared for histological assessment and polymerase chain reaction assay. In an in vitro experiment, embryo kidneys of fetal mice on gestation day 12.5 were used, and CsA (10 µmol/L) was added in the culture of the CsA group. The growth pattern of the ureteric bud and nephrons was assessed by lectin staining. RESULTS:: No significant differences in the weight of embryo (4.54 ± 1.22 vs. 3.26 ± 1.09 mg) were observed between the CsA and control groups, the thickness of the cortical (510.0 ± 30.3 vs. 350.0 ± 29.7 µm, P < 0.05) and nephrogenic zone (272.5 ± 17.2 vs. 173.3 ± 24.0 µm, P < 0.05), and the number of glomeruli (36.5 ± 0.7 vs. 27.5 ± 2.1, P < 0.05) were reduced in the CsA group when compared to the control group. The cell proliferation of Ki-67 positive index between control and CsA group (307.0 ± 20.0 vs. 219.0 ± 25.0, P < 0.05) in the nephrogenic zone was decreased with the increase of apoptotic cells (17.0 ± 2.0 vs. 159.0 ± 33.0, P < 0.05). The mRNA expression of WT-1, Pax2, and Pax8 was downregulated by CsA treatment. As for the in vitro CsA group, the branch number of the ureteric bud was decreased in the CsA-treated group with the nephrons missing in contrast to control after the incubation for 24 h and 72 h (all P < 0.0001). CONCLUSION:: Treatment of CsA suppressed metanephros development in the pregnant mice; however, the potential action of mechanism needs to be further investigated.