Ferroptosis is a non-traditional form of regulated cell death, characterized by iron overload and lipid peroxidation. Exploration of ferroptosis in chronic kidney disease (CKD) has been extremely limited to date. In this study, we established a rat model of CKD by 5/6 nephrectomy, treated CKD rats with the ferroptosis inducer, cisplatin (CDDP), and the ferroptosis inhibitor, deferoxamine mesylate (DFO), and observed the resulting pathologic changes (injury markers and fibrosis) and ferroptotic biochemical indices. Kidney iron deposition, lipid peroxidation, mitochondrial defects, ferroptosis marker induction, and TUNEL staining positivity were detected in CKD group rats. Further, treatment with CDDP or DFO influenced renal injury and fibrosis by affecting ferroptosis, rather than apoptosis, and ferroptosis occurs in the remnant kidney due to disordered iron metabolism. In conclusion, our study shows for the first time that 5/6 nephrectomy induces ferroptosis in the remnant kidney and clarifies the underlying pathogenesis. Moreover, we demonstrate that ferroptosis is involved in CKD progression and represents a therapeutic target in chronic kidney injury and renal fibrosis.

Purpose. We aimed to explore the relationship between the cardiometabolic index (CMI) and cardiovascular disease (CVD) and its subtypes (coronary artery disease and stroke) in patients with hypertension and obstructive sleep apnea (OSA). Methods. We conducted a retrospective cohort study enrolling 2067 participants from the Urumqi Research on Sleep Apnea and Hypertension study. The CMI was calculated as triglyceride to high‐density lipoprotein cholesterol ratio × waist‐to‐height ratio. Participants were divided into three groups (T1, T2, and T3) according to the tertile of CMI. The Kaplan‐Meier method helped to calculate the cumulative incidence of CVD in different groups. We assessed the association of CMI with the risk of CVD and CVD subtypes by estimating hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox models. Results. During a median follow‐up of 6.83 years (interquartile range: 5.92‐8.00 years), 326 incident CVD were identified, including 121 incident stroke and 205 incident coronary heart disease (CHD). Overall, after adjusting for confounding variables, CMI was positively associated with the risk of new‐onset CVD (per SD increment, adjusted HR: 1.31; 95% CI: 1.20, 1.43), new‐onset CHD (per SD increment, adjusted HR: 1.33; 95% CI: 1.20, 1.48), and new‐onset stroke (per SD increment, adjusted HR: 1.27; 95% CI: 1.10, 1.47). Similar results were obtained in various subgroup and sensitivity analyses. Adding CMI to the baseline risk model for CVD improved the C‐index (P < 0.001), continuous net reclassification improvement (P < 0.001), and integrated discrimination index (P < 0.001). Similar results were observed for CHD and stroke. Conclusion. There was a positive association between CMI levels and the risk of new‐onset CVD in patients with hypertension and OSA. This finding suggests that CMI may help identify people at high risk of developing CVD.

Acute and chronic kidney injuries result from structural dysfunction and metabolic disorders of the kidney in various etiologies, which significantly affect human survival and social wealth. Nephropathies are often accompanied by various forms of cell death and complex microenvironments. In recent decades, the study of kidney diseases and the traditional forms of cell death have improved. Nontraditional forms of cell death, represented by ferroptosis and necroptosis, have been discovered in the field of kidney diseases, which have reshuffled the role of traditional cell death in nephropathies. Although interactions between ferroptosis and acute kidney injury (AKI) have been continuously explored, studies on ferroptosis and chronic kidney disease (CKD) remain limited. Here, we have reviewed the therapeutic significance of ferroptosis in AKI and anticipated the curative potential of ferroptosis for CKD in the hope of providing insights into ferroptosis and CKD.

Background: Macrophages are the most abundant infiltrating immune-related stromal cells present in and around tumors, showing different phenotypes and functions. M2 macrophages mainly exert immunosuppressive functions and promote tumor growth. Exosomes are emerging as important mediators of cross-talk between tumor cells and the microenvironment. CircRNAs are novel members of non-coding RNAs that regulate cancer proliferation and progression. However, the mechanism by which exosomal circRNA regulates macrophage polarization in renal cell carcinoma (RCC) is still largely unknown.Methods: RCC-derived exosomes were characterized using transmission electron microscopy and nanoparticle tracking analysis (NTA). CCK-8, wound healing, and Transwell assays were performed to assess whether exosomes would affect the proliferation, migration, and invasion of RCC. Furthermore, we performed a bioinformatics analysis to identify circRNAs in RCC serum-derived exosomes from the GEO database. The fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circSAFB2. Bioinformatics analyses (StarBase 2.0) were used to pool the miRNA targets of circSAFB2. Luciferase assays were performed to verify the direct interactions. Western blotting was used to detect markers of macrophage M2 polarization. Lastly, mouse xenograft and bioluminescence imaging were used to examine the clinical relevance of exosomal circSAFB2 in vivo.Results: We report the circRNA derived from SAFB2 and evaluate its biological function in promoting the immune escape of RCC. We found that circSAFB2 was highly expressed in RCC tissues and RCC-derived exosomes. Furthermore, we demonstrated that exosomal circSAFB2 mediates the polarization of M2 macrophages through the miR-620/JAK1/STAT3 axis to promote RCC metastasis.Conclusions: Our data first demonstrated that circSAFB2 leads to immune escape from RCC by mediating M2 macrophage polarization via the miR-620/JAK1/STAT3 axis. These findings indicate a novel molecular mechanism of exosomal circSAFB2 in the progression of RCC and implicate circSAFB2 as a target for exosome-mediated tumor immune evasion.

Purpose: Puerarin (PR), a Chinese medicine rich in natural components, has been reported to display anti-fibrotic, antioxidant, anti-inflammatory and immunomodulatory properties. However, the protective mechanism of PR against unilateral ureteral obstruction (UUO)-mediated renal injury is not fully clarified. Therefore, the aim of this study was to investigate the effects of PR on UUO mice and its possible mechanisms. Methods: A total of 32 C57BL/6 mice were divided randomly into four groups (n=8): i) sham-operated group (Sham); ii) UUO group (UUO); iii) UUO + PR 50 mg/kg/day (UUO + PRL); and iv) UUO + PR 100 mg/kg/day (UUO + PRH). Continuous gavage administration for 14 days starting one week postoperatively, while the mice in Sham and UUO groups were given equal amounts of vehicle by the same means. All mice were then sacrificed and serum, 24-hour urine and tissue specimens were collected for renal function, histopathology, Western blot, immunohistochemistry. Results: Renal function and histopathology revealed that PR improved UUO-mediated renal dysfunction and partially reversed tubular injury and tubulointerstitial fibrosis. Additionally, according to the results of Western blot and immunohistochemistry, PR inhibited the expression of inflammatory factors including IL-1β, IL-6, MCP-1 and ECM-related proteins including α-SMA, COL I and VIM. More importantly, the expression of fibrotic pathways TGF-β 1, Smad3, p-Smad3 and inflammatory pathways NF-κB p65, NF-κB p-p65, STAT3, p-STAT3 were inhibited to various extents under the PR treatment, while Smad7 was upregulated. Conclusion: These findings indicate that PR may inhibit the recruitment of inflammatory factors and extracellular matrix (ECM) deposition through the regulation of the NF-κB p65/STAT3 and TGFβ 1/Smads pathways, which alleviates the UUO-induced inflammatory and fibrotic response, thereby reversing renal injury.