Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

/pdf/mitochondrial-iron-overload-mediated-inhibition-of-nrf2-ho-1-40wr68m5f8.pdf

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Aristolochic acid (AA) is a generic term that describes a group of structurally related compounds found in the Aristolochiaceae plants family. These plants have been used for decades to treat various diseases. However, the consumption of products derived from plants containing AA has been associated with the development of nephropathy and carcinoma, mainly the upper urothelial carcinoma (UUC). AA has been identified as the causative agent of these pathologies. Several studies on mechanisms of action of AA nephrotoxicity have been conducted, but the comprehensive mechanisms of AA-induced nephrotoxicity and carcinogenesis have not yet fully been elucidated, and therapeutic measures are therefore limited. This review aimed to summarize the molecular mechanisms underlying AA-induced nephrotoxicity with an emphasis on its enzymatic bioactivation, and to discuss some agents and their modes of action to reduce AA nephrotoxicity. By addressing these two aspects, including mechanisms of action of AA nephrotoxicity and protective approaches against the latter, and especially by covering the whole range of these protective agents, this review provides an overview on AA nephrotoxicity. It also reports new knowledge on mechanisms of AA-mediated nephrotoxicity recently published in the literature and provides suggestions for future studies.

Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches.

Aristolochic acid (AA) is a compound extracted from the Aristolochia species of herbs. AA exposure is associated with kidney injury known as aristolochic acid nephropathy (AAN). Proximal tubular epithelial cell (PTEC) is the primary target of AA and rich in mitochondria. Recently, increasing evidence suggests that mitochondrial dysfunction plays a critical role in the pathogenesis of kidney disease. However, the status of mitochondrial function in PTEC after exposure to AA remains largely unknown. The aim of this study was to explore the effect of aristolochic acid I (AAI) on cell apoptosis and mitochondrial function in PTEC. Normal rat kidney-52E (NRK-52E) cells were exposed to different concentrations of AAI for different time periods. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, cell apoptosis was analyzed by flow cytometry, and the expression of cleaved caspase-3 by Western blotting. Mitochondrial function was evaluated by reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial DNA (mtDNA) copy number, and adenosine triphosphate (ATP). It was found that AAI reduced cell viability and increased cell apoptosis in a dose- and time-dependent manner. In parallel to increased apoptosis, NRK-52E cell manifested signs of mitochondrial dysfunction in response to AAI treatment. The data indicated that AAI could increase ROS level, lower MMP, decrease mtDNA copy number, and reduce ATP production. In addition, Szeto-Schiller 31, a mitochondria-targeted antioxidant peptide, attenuated AAI-induced mitochondrial dysfunction and apoptosis. Our study depicted significant aberrant of mitochondrial function in AAI-treated NRK-52E cell, which suggested that mitochondrial dysfunction may be involved in AAI-induced apoptosis in PTEC.

Mitochondrial dysfunction is involved in aristolochic acid I-induced apoptosis in renal proximal tubular epithelial cells:

Inflammation plays a pivotal in the occurrence and development of coronary heart disease (CHD). We aim to investigate the association between the Dietary Inflammatory Index (DII) and CHD in the present study. In this cross-sectional study, adult participants from the National Health and Nutrition Examination Survey (NHANES) (1999–2018) were enrolled. The social demographic information, lifestyle factors, blood biochemical measurements, dietary information, and CHD status of all the participants were systematically collected. Multivariable logistic regression was adopted to investigate the association between the risk of CHD and the DII. Besides, restricted cubic spline (RCS) analysis was used to explore whether there was a nonlinear association of the DII and CHD. Subgroup analysis stratified by sex, age, race/ethnicity, and BMI was conducted to evaluate the association of the DII and CHD among different populations. A total of 45,306 adults from NHANES (1999–2018) were included. Compared with individuals without CHD, the DIIs of the participants with CHD were significantly elevated. A positive association was observed between the DII and CHD in multivariable logistic analysis after adjusting for age, sex, race/ethnicity, education levels, smoking, drinking, diabetes, hypertension, and body mass index (BMI). Results of RCS analysis suggested a nonlinear relationship between the DII and CHD. In addition, the increment of the DII had a greater impact on female individuals compared with male individuals. The DII is closely associated with the risk of CHD. For better prevention and treatment of CHD, more attention should be paid to controlling dietary inflammation.

/pdf/dietary-inflammatory-index-and-its-association-with-the-3ukkg4ba.pdf

Dietary Inflammatory Index and Its Association with the Prevalence of Coronary Heart Disease among 45,306 US Adults

Diabetic nephropathy (DN) is a renal complication of diabetic hyperglycemia. The Signal transducer and activator of transcription 3 (Stat3) is a center molecule of the chronic inflammation causing DN progression. Therefore, the study investigated the possible inhibitory effects of Rutin (Ru) and Selenium (Se), formulated as nanoparticles (SeNPs), on Stat3 pathway in streptozotocin (STZ)-induced DN in Sprague-Dawley rats. Ru (100 mg/kg/orally) and SeNPs (equivalent to 5 mg of Se/kg/orally) were given as treatment for eight weeks. An assessment of fasting blood glucose, renal function biomarkers, GSH, and MDA was carried out spectrophotometrically. ELISA assessment of renal IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 was performed. Sirt-1, Nrf-2, and HO-1 were assessed immunohistochemically. DN group receiving Ru + SeNPs showed a decrease in fasting blood glucose, serum creatinine, and urea (163.8 ± 22.8, 0.54 ± 0.1, and 53.6 ± 25.7 mg/dl, respectively), compared to the DN group (443.8 ± 42.72, 1.58 ± 0.4, and 281.8 ± 47.35 mg/dl, respectively). In addition, it exhibited elevation in the levels of Sirt-1, Nrf-2 and HO-1 compared to the DN group. Finally, Ru + SeNPs exhibited a significant reduction in IL-6, NF-κB, TNF-α, Jak-2, and p-Stat3 (42.8 ± 10.3, 1.2 ± 0.1, 53.4 ± 3.87, 0.8 ± 0.06 and 1.1 ± 0.2 U/g tissue, respectively) when compared to the DN group (155.3 ± 13.97, 2.8 ± 0.3, 105.5 ± 32.84, 2.03 ± 0.2 and 2.56 ± 0.15 U/g tissue, respectively). Therefore, combining Ru with SeNPs has a potential renoprotective effect against DN by upregulating Nrf-2/HO-1 and downregulating Jak-2/Stat3 Pathways. 

Rutin and selenium nanoparticles protected against STZ-induced diabetic nephropathy in rats through downregulating Jak-2/Stat3 pathway and upregulating Nrf-2/HO-1 pathway.

Cardamomin protects from diabetes-induced kidney damage through modulating PI3K/AKT and JAK/STAT signaling pathways in rats.

FOXC1 Aggravates the Ischemia‐Reperfusion Induced Injury in Renal Tubular Epithelial Cells by Activating NF‐κB/NLRP3 Signaling

Protective role of relaxin in a mouse model of aristolochic acid nephropathy

Supplemental Digital Content is Available in the Text. Abstract: Circular RNAs (circRNAs) have been verified as vital regulators in various diseases, including membranous nephropathy (MN). Therefore, the role of circ_CDYL in podocyte apoptosis and MN was investigated. The real-time quantitative polymerase chain reaction was performed to measure the expression of circ_CDYL, microRNA-149-5p (miR-149-5p), and tumor necrosis factor superfamily member 11 (TNFSF11) in podocytes. In addition, angiotensin II (Ang II) was used to induce apoptosis of podocytes. The apoptosis-related protein expression was quantified by western blot assay. The apoptosis of podocytes was evaluated by flow cytometry assay. The interaction relationship between miR-149-5p and circ_CDYL or TNFSF11 was confirmed by dual-luciferase reporter assay. Circ_CDYL was significantly overexpressed in MN patients and Ang II–induced podocytes compared with control groups. Importantly, loss-of-functional experiments indicated that knockdown of circ_CDYL protected podocytes from Ang II–induced apoptosis. MiR-149-5p was verified as target of circ_CDYL and negatively correlated with circ_CDYL expression in MN patients. Knockdown of circ_CDYL–mediated effects on Ang II–induced podocyte cells were abolished by silencing miR-149-5p. Besides, the upregulation of miR-149-5p could suppress apoptosis in Ang II–induced podocyte cells by targeting TNFSF11. Under Ang II stimulation, the upregulation of TNFSF11 could increase the expression of TNFSF11 and induce apoptosis in circ_CDYL-silencing podocytes. Our results confirmed that circ_CDYL specifically targeted miR-149-5p/TNFSF11 pathway to regulate Ang II–induced apoptosis in podocytes, which might be useful diagnostic biomarkers in MN.

Knockdown of circ_CDYL Contributes to Inhibit Angiotensin II–Induced Podocytes Apoptosis in Membranous Nephropathy via the miR-149-5p/TNFSF11 Pathway

Late-onset fabry disease presenting with unexplained renal failure, left ventricular hypertrophy, and recurrent syncope: a case report

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