SAA1 deficiency alleviates cardiac remodeling by inhibiting NF-κB/p38/JNK and TGFß/Smad pathways.

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid-binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1-deficient (SAA1-/- ), and wild-type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1-/- mice displayed a lower level of cardiac fibrosis than wild-type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild-type-sham and knockout-sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study.

The automatic detection of diabetic kidney disease from retinal vascular parameters combined with clinical variables using artificial intelligence in type-2 diabetes patients.

BACKGROUND: Diabetic kidney disease (DKD) has become the largest cause of end-stage kidney disease. Early and accurate detection of DKD is beneficial for patients. The present detection depends on the measurement of albuminuria or the estimated glomerular filtration rate, which is invasive and not optimal; therefore, new detection tools are urgently needed. Meanwhile, a close relationship between diabetic retinopathy and DKD has been reported; thus, we aimed to develop a novel detection algorithm for DKD using artificial intelligence technology based on retinal vascular parameters combined with several easily available clinical parameters in patients with type-2 diabetes. METHODS: A total of 515 consecutive patients with type-2 diabetes mellitus from Xiangyang Central Hospital were included. Patients were stratified by DKD diagnosis and split randomly into either the training set (70%, N = 360) or the testing set (30%, N = 155) (random seed = 1). Data from the training set were used to develop the machine learning algorithm (MLA), while those from the testing set were used to validate the MLA. Model performances were evaluated. RESULTS: The MLA using the random forest classifier presented optimal performance compared with other classifiers. When validated, the accuracy, sensitivity, specificity, F1 score, and AUC for the optimal model were 84.5%(95% CI 83.3-85.7), 84.5%(82.3-86.7), 84.5%(82.7-86.3), 0.845(0.831-0.859), and 0.914(0.903-0.925), respectively. CONCLUSIONS: A new machine learning algorithm for DKD diagnosis based on fundus images and 8 easily available clinical parameters was developed, which indicated that retinal vascular changes can assist in DKD screening and detection.

Performance of urinary vitamin D-binding protein in diabetic kidney disease: a meta-analysis.

Objective: To systematically evaluate the correlation between urinary vitamin D-binding protein (VDBP) and diabetic kidney disease and to evaluate the relationship between urinary VDBP and the albumin-to-creatinine ratio (ACR), renal function indicators [estimate glomerular filtration rate (eGFR), creatinine (CR), blood urea nitrogen (BUN)] and glycaemic control indices [glycated hemoglobin (HbA1c), fasting plasma glucose (FPG)].Methods: We searched the CNKI, Wanfang, VIP, CBM, PubMed, Cochrane Library, Embase and Web of Science databases up to May 31, 2023, for relevant literature. RevMan 5.3 software was used for the meta-analysis.Results: Ultimately, 9 articles were included. Due to heterogeneity in the pooled results, the random-effects model was chosen. Meta-analysis results showed that the urinary VDBP concentrations in the normal albuminuria diabetes group were significantly higher than those in the healthy control group [SMD 1.52, 95% CI (0.84, 2.19), p < 0.00001]. The urinary VDBP concentrations in the microalbuminuria diabetes group were significantly higher than those in the normal albuminuria diabetes group [SMD 1.81, 95% CI (1.40, 2.21), p < 0.00001]. The urinary VDBP concentrations in the macroalbuminuria diabetes group were also significantly higher than those in the microalbuminuria diabetes group [SMD 1.51, 95% CI (1.05, 1.96), p < 0.00001]. In addition, urinary VDBP was positively correlated with the ACR, CR, BUN and HbA1c [Summary r = 0.73, 95% CI (0.54, 0.85), p < 0.0001; Summary r = 0.38, 95% CI (0.10, 0.61), p = 0.009; Summary r = 0.37, 95% CI (0.16, 0.55), p = 0.0008; Summary r = 0.40, 95% CI (0.13, 0.62), p = 0.005, respectively] and tended to be negatively correlated with the eGFR [Summary r = -0.64, 95% CI (-0.92, 0.10), p = 0.08] but was not significantly correlated with the FPG [Summary r = 0.16, 95% CI (-0.03, 0.33), p = 0.10]. Sensitivity analysis showed that our pooled results are robust.Conclusion: Urinary VDBP may be used as a novel biomarker for the early diagnosis of DKD and can be used to assess the severity of DKD.

The Correlation between Ferroptosis and m6A Methylation in Patients with Acute Kidney Injury.

OBJECTIVE: The present research analyzed the correlation between N6-methyladenosine (m6A) methylation and ferroptosis associated genes (FAGs) in acute kidney injury (AKI) patients. METHODS: Bioinformatics analysis of microarray profiles (GSE30718) was performed to select differential expression genes (DEGs). FAGs are derived from systematic analysis of the aberrances and functional implications. The m6A methylation related genes were derived from the molecular characterization and clinical significance of m6A modulators. The multi-gene correlation of ferroptosis and M6A methylation modification was displayed. Then, the CIBERSORT algorithm was used to analyze the proportions of 22 immune cell infiltration. RESULTS: In total, 349 DEGs were extracted between the AKI and control samples, among which 172 genes were upregulated and 177 were downregulated. FAGs (SLC1A5, CARS, SAT1, ACSL4, NFE2L2, TFRC, and MT1G) and m6A methylation related genes (YTHDF3, WTAP, and IGF2BP3) were significantly increased in AKI patients (p < 0.05). FAGs (SAT1, ACSL4, and NFE2L2) were positively correlated with the expression level of m6A methylation genes (p < 0.05). NFE2L2 has high diagnostic value, and the level of NFE2L2 was negatively correlated with the degree of follicular helper T (TFH) cell infiltration. CONCLUSION: Our research could provide a new theoretical basis for the pathogenesis and immune mechanism of AKI.

The recruitment mechanisms and potential therapeutic targets of podocytes from parietal epithelial cells.

Podocytes are differentiated postmitotic cells which cannot be replaced after podocyte injury. The mechanism of podocyte repopulation after injury has aroused wide concern. Parietal epithelial cells (PECs) are heterogeneous and only a specific subpopulation of PECs has the capacity to replace podocytes. Major progress has been achieved in recent years regarding the role and function of a subset of PECs which could transdifferentiate toward podocytes. Additionally, several factors, such as Notch, Wnt/ß-catenin, Wilms' tumor-1, miR-193a and growth arrest-specific protein 1, have been shown to be involved in these processes. Finally, PECs serve as a potential therapeutic target in the conditions of podocyte loss. In this review, we discuss the latest observations and concepts about the recruitment of podocytes from PECs in glomerular diseases as well as newly identified mechanisms and the most recent treatments for this process.

Vascular calcification: New insights into endothelial cells.

Vascular calcification, a common pathological basis of vascular disease, is caused by various diseases and is an independent risk factor for cardiovascular events. Therefore, elucidating the pathogenesis of vascular calcification has significant clinical benefits. It is generally believed that vascular calcification is similar to the processes of bone development and cartilage formation. The transformation of vascular smooth muscle cells into osteoblast- and chondrocyte-like cells is a key event. However, recent studies have found that under certain conditions, endothelial cells participate in vascular calcification via endothelial-mesenchymal transition, cytokine secretion, extracellular vesicle synthesis, angiogenesis regulation and hemodynamics. This review aims to explore the relationship between endothelial cells and vascular calcification and to provide a theoretical basis and new ideas for the active prevention and treatment of vascular calcification in the clinic.

SGLT2i: beyond the glucose-lowering effect.

Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a new type of glucose-lowering drug that can reduce blood glucose by inhibiting its reabsorption in proximal tubules and by promoting urinary glucose excretion. SGLT2i are widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). In recent studies, SGLT2i were found to not only reduce blood glucose but also protect the heart and kidney, which can significantly reduce cardiovascular events, delay the progression of renal failure, greatly improve the quality of life of patients, and reduce medical expenses for families and society. As adverse cardiac and renal events are the most common and serious complications of T2DM, it is very important to understand the cardio- and renoprotective mechanisms of SGLT2i. This article reviews the historical development, pharmacological mechanism, heart and kidney protection and safety of SGLT2i. The information presented provides a theoretical basis for the clinical prevention and treatment of diabetes and its complications and for the development of new glucose-lowering drugs.

Bioinformatics-based discovery of the urinary BBOX1 mRNA as a potential biomarker of diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the world. Emerging evidence has shown that urinary mRNAs may serve as early diagnostic and prognostic biomarkers of DKD. In this article, we aimed to first establish a novel bioinformatics-based methodology for analyzing the "urinary kidney-specific mRNAs" and verify their potential clinical utility in DKD. METHODS: To select candidate mRNAs, a total of 127 Affymetrix microarray datasets of diabetic kidney tissues and other tissues from humans were compiled and analyzed using an integrative bioinformatics approach. Then, the urinary expression of candidate mRNAs in stage 1 study (n = 82) was verified, and the one with best performance moved on to stage 2 study (n = 80) for validation. To avoid potential detection bias, a one-step Taqman PCR assay was developed for quantification of the interested mRNA in stage 2 study. Lastly, the in situ expression of the selected mRNA was further confirmed using fluorescent in situ hybridization (FISH) assay and bioinformatics analysis. RESULTS: Our bioinformatics analysis identified sixteen mRNAs as candidates, of which urinary BBOX1 (uBBOX1) levels were significantly upregulated in the urine of patients with DKD. The expression of uBBOX1 was also increased in normoalbuminuric diabetes subjects, while remained unchanged in patients with urinary tract infection or bladder cancer. Besides, uBBOX1 levels correlated with glycemic control, albuminuria and urinary tubular injury marker levels. Similar results were obtained in stage 2 study. FISH assay further demonstrated that BBOX1 mRNA was predominantly located in renal tubular epithelial cells, while its expression in podocytes and urothelium was weak. Further bioinformatics analysis also suggested that tubular BBOX1 mRNA expression was quite stable in various types of kidney diseases. CONCLUSIONS: Our study provided a novel methodology to identify and analyze urinary kidney-specific mRNAs. uBBOX1 might serve as a promising biomarker of DKD. The performance of the selected urinary mRNAs in monitoring disease progression needs further validation.

A rat model of SHPT with bone abnormalities in CKD induced by adenine and a high phosphorus diet.

The study of parathyroid hyperplasia with bone disease as a critical manifestation of chronic kidney disease-mineral and bone disorders (CKD-MBDs) is challenging due to the lack of a suitable research model. Here, we established a rat model with secondary hyperparathyroidism (SHPT) and bone disease induced by adenine and a high phosphorous diet and analyzed the skeletal characteristics. We performed blood analysis, emission computed tomography (ECT), dual energy X-ray absorptiometry (DEXA), micro-computed tomography (micro-CT), bone histomorphometry, and bone mechanical tests. The CKD rats with SHPT induced by adenine and a high phosphorus diet showed severe abnormalities in calcium and phosphorus metabolism and exhibited parathyroid hyperplasia. The bone mineral density (BMD) of femurs and lumbar vertebrae was significantly lower in the CKD rats than in the control (CTL) rats. The cortical and trabecular bone parameters of femurs showed significant bone loss. In addition, we found decreases in ultimate force, work to failure, stiffness, and elastic modulus in the CKD rats. In conclusion, our findings demonstrated that the CKD rats with SHPT induced by adenine and a high phosphorus diet may serve as a useful model for skeletal analysis in CKD with SHPT.

Cetuximab versus nimotuzumab for the treatment of advanced nasopharyngeal carcinoma: A network meta-analysis.

PURPOSE: We conducted a network meta-analysis to evaluate the efficacy and toxicity of cetuximab and nimotuzumab in the treatment of advanced nasopharyngeal carcinoma (NPC). METHODS: A systematic literature search was performed though Pubmed, Embase, Cochran Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical (CBM) and Wanfang databases. Totally, 19 randomized controlled trials (RCTs) (n=1201) met the study selection criteria and were incorporated in this network meta-analysis. RESULTS: Compared with cetuximab, the results of network meta-analysis indicated that nimotuzumab may achieve higher complete remission rate (CRR) or overall remission rate (ORR) of the primary tumor, but no difference was noticed in 1- and 2-year overall survival (OS) rate and certain toxicities such as myelosuppression, radiodermatitis, mucositis and gastrointestinal reactions. Although nimotuzumab increased the 3-year OS rate, compared with cetuximab, this result needs to be interpreted cautiously because of the studies' heterogeneity. CONCLUSION: Even though we didn't find significant difference between cetuximab and nimotuzumab in terms of survival outcomes, nimotuzumab is more advantageous in short-term efficacy.

Identification of the communal pathogenesis and immune landscape between viral myocarditis and dilated cardiomyopathy.

AIMS: Studies have confirmed that viral myocarditis (VMC) is one of the risk factors for dilated cardiomyopathy (DCM). The molecular mechanisms underlying the progression from VMC to DCM remain unclear and require further investigation. METHODS AND RESULTS: The mRNA microarray datasets GSE57338 (DCM) and GSE1145 (VMC) were obtained from the Gene Expression Omnibus database. The candidate key genes were further screened using weighted correlation network analysis (WGCNA), protein-protein interaction and external dataset validation, and the correlation between the candidate key genes and immune cells and the signalling pathways of the candidate key genes were observed by enrichment analysis and immune infiltration analysis. The expression of key genes was validated in the external dataset GSE35182. The crosstalk genes between DCM and VMC were mainly enriched in 'transcriptional misregulation in cancer', 'FoxO signalling pathway', 'AGE-RAGE signalling pathway in diabetic complications', 'thyroid hormone signalling pathway', 'AMPK signalling pathway', and other signalling pathways. The immune infiltration analysis indicated that VMC was mainly associated with resting dendritic cells and M0 macrophages, while DCM was mainly associated with monocytes, M0 macrophages, CD8+ T cells, resting CD4 memory T cells, naive CD4+ T cells, and resting mast cells. In DCM-related dataset GSE57338 and VMC-related dataset GSE1145, a total of 18 candidate key genes were differentially expressed. BLC6, FOXO1, and UBE2M were identified as the key genes that lead to the progression from VMC to DCM by GSE35182. CONCLUSIONS: Three key genes (BLC6, FOXO1, and UBE2M) were identified and provided new insights into the diagnosis and treatment of VMC with DCM.

Risk factors of disease activity and renal damage in patients with systemic lupus erythematosus.

PURPOSE: To evaluate the clinical features of patients with Systemic Lupus Erythematosus (SLE) and explore the risk factors of disease activity and renal damage. METHODS: A retrospective study involving 194 patients were performed. Patients were divided into lupus nephritis (LN) group (63.40%) and non-LN group (36.60%), different disease activity group, and different renal function group according to the clinical data. Multivariate logistic regression analysis showed that albumin (ALB), uric acid (UC), total cholesterol (TC), and anti-dsDNA antibodies were the influencing factors of LN in patients with SLE (P < 0.05); ALB, UC, and complement 3(C3) were the influencing factors of lupus disease activity (P < 0.05); UC, C3, and hemoglobin (HB) were the influencing factors of abnormal renal function in SLE patients. RESULTS: The results of the ROC curve showed that ALB, UA, and TC had certain predictive value for combined LN in patients with SLE, and the predictive value of ALB was greater than that of TC (P < 0.05); ALB, UA, and C3 being predictors of the activity of patients with SLE; BUN, UA, and HB all had certain predictive value for the abnormal renal function in patients with LN. SLE patients have the high incidence of renal impairment. CONCLUSION: The results of this study suggest that patients with SLE should regularly monitor the levels of ALB, UA, TC, C3, and HB, as well as pay attention to the intervention of hyperlipidemia and hyperuricemia in patients with SLE to better control disease progression.

Expression characteristics of lipid metabolism-related genes and correlative immune infiltration landscape in acute myocardial infarction.

Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to "leukotriene production involved in inflammatory response", "lipoxygenase pathway", "metabolic pathways", and "regulation of lipolysis in adipocytes" pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.

Scavenger Receptor Class B Type I Deficiency Induces Iron Overload and Ferroptosis in Renal Tubular Epithelial Cells via Hypoxia-Inducible Factor-1α/Transferrin Receptor 1 Signaling Pathway.

Aims: Scavenger receptor class B type I (SRBI) promotes cell cholesterol efflux and the clearance of plasma cholesterol. Thus, SRBI deficiency causes abnormal cholesterol metabolism and hyperlipidemia. Studies have suggested that ferroptosis is involved in lipotoxicity; however, whether SRBI deficiency could induce ferroptosis remains to be investigated. Results: We knocked down or knocked out SRBI in renal HK-2 cells and C57BL/6 mice to determine the expression levels of ferroptosis-related regulators. Our results demonstrated that SRBI deficiency upregulates transferrin receptor 1 (TFR1) expression and downregulates ferroportin expression, which induces iron overload and subsequent ferroptosis in renal tubular epithelial cells. TFR1 is known to be regulated by hypoxia-inducible factor-1α (HIF-1α). Next, we investigated whether SRBI deletion affected HIF-1α. SRBI deletion upregulated the mRNA and protein expression of HIF-1α, and promoted its translocation to the nucleus. To determine whether HIF-1α plays a key role in SRBI-deficiency-induced ferroptosis, we used HIF-1α inhibitor and siHIF-1α in HK-2 cells, and found that downregulation of HIF-1α prevented SRBI-silencing-induced TFR1 upregulation and iron overload, and eventually reduced ferroptosis. The underlying mechanism of HIF-1α activation was explored next, and the results showed that SRBI knockout or knockdown may upregulate the expression of HIF-1α, and promote HIF-1α translocation from the cytoplasm into the nucleus via the PKC-ß/NF-κB signaling pathway. Innovation and Conclusion: Our study showed, for the first time, that SRBI deficiency induces iron overload and subsequent ferroptosis via the HIF-1α/TFR1 pathway.

The roles of heme oxygenase-1 in renal disease.

Heme oxygenase (HO), a heat shock protein containing hemoglobin, is an important enzyme in heme catabolism. It is involved in cell homeostasis and has anti-inflammatory, antioxidant, anti-apoptosis, immunomodulation, and other functions. It is expressed at a modest level in most normal tissues. When the body suffers from ischemia hypoxia, injury, toxins, and other nociceptive stimuli, the expression increases, which can transform the oxidative microenvironment into an antioxidant environment to promote tissue recovery from damage. In recent years, research has continued to verify its value in a variety of human bodily systems. It is also regarded as a key target for the treatment of numerous disorders. With the advancement of studies, its significance in renal disease has gained increasing attention. It is thought to have a significant protective function in preventing acute kidney injury and delaying the progression of chronic renal diseases. Its protective mechanisms include anti-inflammatory, antioxidant, cell cycle regulation, apoptosis inhibition, hemodynamic regulation, and other aspects, which have been demonstrated in diverse animal models. Furthermore, as a protective factor, its potential therapeutic efficacy in renal disease has recently become a hot area of research. Although a large number of preclinical trials have confirmed its therapeutic potential in reducing kidney injury, due to the problems and side effects of HO-1 induction therapy, its efficacy and safety in clinical application need to be further explored. In this review, we summarize the current state of research on the mechanism, location, and treatment of HO and its relationship with various renal diseases.

Association of Obesity Indices with Diabetic Kidney Disease and Diabetic Retinopathy in Type 2 Diabetes: A Real-World Study.

Background: Diabetic microvascular complications mainly include diabetic kidney disease (DKD) and diabetic retinopathy (DR). Obesity was recognized as a risk factor for DKD, while the reported relationship between obesity and DR was inconsistent. Moreover, whether the associations can be attributed to C-peptide levels is unknown. Methods: Data from 1142 sequential inpatients with T2DM at Xiangyang Central Hospital between June 2019 and March 2022 were extracted retrospectively from the electronic medical record system. The associations between four obesity indices (body mass index (BMI), waist-hip circumference ratio (WHR), visceral fat tissue area (VFA), and subcutaneous fat tissue area (SFA)) and DKD and DR were evaluated. Whether the associations can be attributed to C-peptide levels was also explored. Results: Obesity was a risk factor for DKD after adjusting for sex, HbA1c, TG, TC, HDL, LDL, smoking history, education, duration of diabetes, and insulin use (obesity indices: BMI (OR 1.050: 95% CI: 1.008-1.094; P = 0.020); WHR (OR 10.97; 95% CI: 1.250-92.267; P = 0.031); VFA (OR 1.005; 95% CI: 1.001-1.008; P = 0.008)), but it became insignificant after further adjusting for fasting C-peptide. The associations between BMI, WHR, VFA, and DKD might be U-shaped. Obesity and FCP tended to protect against DR; however, they became insignificant after adjusting for multiple potential confounders. C2/C0 (the ratio of the postprandial serum C-peptide to fasting C-peptide) was a protective factor for both DKD (OR 0.894, 95% CI: 0.833-0.959, P < 0.05) and DR (OR 0.851, 95% CI: 0.787-0.919; P < 0.05). Conclusions: Obesity was a risk factor for DKD, and the effect may be attributable to C-peptide, which represents insulin resistance. The protective effect of obesity or C-peptide on DR was not independent and could be confounded by multiple factors. Higher C2/C0 was associated with both decreased DKD and DR.

Expression Pattern and Molecular Mechanism of Oxidative Stress-Related Genes in Myocardial Ischemia-Reperfusion Injury.

(1) Background: The molecular mechanism of oxidative stress-related genes (OSRGs) in myocardial ischemia-reperfusion injury (MIRI) has not been fully elucidated. (2) Methods: Differential expression analysis, enrichment analysis, and PPI analysis were performed on the MIRI-related datasets GSE160516 and GSE61592 to find key pathways and hub genes. OSRGs were obtained from the Molecular Signatures Database (MSigDB). The expression pattern and time changes of them were studied on the basis of their raw expression data. Corresponding online databases were used to predict miRNAs, transcription factors (TFs), and therapeutic drugs targeting common differentially expressed OSRGs. These identified OSRGs were further verified in the external dataset GSE4105 and H9C2 cell hypoxia-reoxygenation (HR) model. (3) Results: A total of 134 DEGs of MIRI were identified which were enriched in the pathways of "immune response", "inflammatory response", "neutrophil chemotaxis", "phagosome", and "platelet activation". Six hub genes and 12 common differentially expressed OSRGs were identified. A total of 168 miRNAs, 41 TFs, and 21 therapeutic drugs were predicted targeting these OSRGs. Lastly, the expression trends of Aif1, Apoe, Arg1, Col1a1, Gpx7, and Hmox1 were confirmed in the external dataset and HR model. (4) Conclusions: Aif1, Apoe, Arg1, Col1a1, Gpx7, and Hmox1 may be involved in the oxidative stress mechanism of MIRI, and the intervention of these genes may be a potential therapeutic strategy.

Empagliflozin attenuates the renal tubular ferroptosis in diabetic kidney disease through AMPK/NRF2 pathway.

Renal tubular damage plays a key role in the pathogenesis of diabetic kidney disease (DKD), and one of the main pathological process associated with DKD in diabetic mice is the ferroptosis, a novel form of cell death caused by iron-dependent lipid peroxidation. Several researches suggested that empagliflozin may treat renal injury, but its effects on diabetic-related ferroptosis and underlying mechanisms were not fully elucidated. In this study, the influence of empagliflozin on renal injury was evaluated in vivo and in vitro in a mouse model and in high-glucose (HG) or Erastin-stimulated renal HK-2 cell line, respectively. Ferroptosis-related markers were assessed, including GSH, labile iron levels, and ferroptosis regulators by Western blot, qRT-PCR, immunohistochemistry, and immunofluorescence. The level of malondialdehyde (MDA) and the fluorescence intensity of BODIPY probe indicated the level of lipid peroxidation. It was demonstrated that solute carrier family 7, member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were less expressed in renal biopsy samples from patients affected by DKD than in those from non-diabetic renal disease patients (NDRD), proving the ferroptosis of tubular epithelial cells in case of DKD. Furthermore, empagliflozin markedly decreased the ferroptosis impairment in DKD mice, as well as in HG model of HK-2 cells. Our investigations showed the ability of empagliflozin to suppress ferroptosis was partially countered by AMP-activated protein kinase (AMPK) inhibitor, which led to a reduction of the nuclear translocation of the antioxidant transcription factor NFE2-related factor 2 (NRF2) and downregulation of target genes such as GPX4, ferritin heavy chain 1 (FTH1), and SLC7A11, while AMPK agonists were responsible for the enhancement of the protective effects of empagliflozin. Taken together, our findings showed that empagliflozin may prevent the development of ferroptosis by promoting the AMPK-mediated NRF2 activation pathway, providing important insights for possible novel treatment approaches for DKD.

Comparison of Nonalbuminuric and Albuminuric Diabetic Kidney Disease Among Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Diabetic kidney disease (DKD) is one of most common complications of diabetes. Recently, the classical phenotype of DKD, which is characterized by albuminuria preceding renal insufficiency, has been challenged since a subset of diabetic patients with renal insufficiency but without albuminuria has been increasingly reported. However, the available evidence is inconsistent. Thus, the present systematic review will assess and summarize the available data regarding nonalbuminuric diabetic kidney disease (NADKD). Methods: PubMed, Embase, and Cochrane were searched for clinical trials related to NADKD. The results were limited to full-text articles published in English, without restrictions on the publication time. The quality of clinical trials was appraised, and the data were extracted. Meta-analysis was conducted using a random-effects model. Descriptive analysis was performed if the data were insufficient. Results: A final total of 31 articles were included in this review. The meta-analysis of 18 studies showed that compared with albuminuric DKD, patients with NADKD were older (MD = 1.04 years old, 95% CI [0.52, 1.57], p < 0.05); were more often women (Male RR = 0.74, 95% CI [0.68, 0.81], p < 0.05); had shorter diabetes duration (MD = -2.9 years, 95% CI [-3.63, -2.18], p < 0.05), lower HbA1c levels (MD = -0.34%, 95% CI [-0.42, -0.25], p < 0.05), and lower blood pressure (systolic blood pressure MD = -6.21 mmHg, 95% CI [-9.41, -3.0], p < 0.05; diastolic blood pressure MD = -1.27 mmHg, 95% CI [-2.15, 4.0], p < 0.05); less frequently experienced diabetic retinopathy (RR = 0.58, 95% CI [0.51, 0.67], p < 0.05); and less frequently used renin-angiotensin-aldosterone system (RAAS) inhibitors. The underlying pathology of NADKD might be different from that of the classic phenotype of DKD, which is associated with more advanced tubulointerstitial and vascular lesions but mild typical glomerular lesions. The annual estimated glomerular filtration rate decline tended to be lower in patients with NADKD than in those with albuminuric DKD. The risk for cardiovascular disease, end-stage renal disease, and all-cause death was lower for patients with NADKD than patients with albuminuric DKD. Conclusions: The prevalence of NADKD has increased in recent decades, and its characteristics, pathology, and prognosis are different from those of albuminuric DKD; thus, diagnosis and treatment strategies should be different. More attention should be given to this phenotype.

Targeting ferroptosis in acute kidney injury.

Acute kidney injury (AKI) is a major public health problem with high incidence and mortality. As a form of programmed cell death (PCD), ferroptosis could be considered as a process of iron accumulation and enhanced lipid peroxidation. Recently, the fundamental roles of ferroptosis in AKI have attracted much attention. The network mechanism of ferroptosis in AKI and its roles in the AKI to chronic kidney disease (CKD) transition is complicated and multifactorial. Strategies targeting ferroptosis show great potential. Here, we review the research progress on ferroptosis and its participation in AKI. We hope that this work will provide clues for further studies of ferroptosis in AKI.