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Oxidative Medicine and Cellular... 2019Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) in western countries. Notably, it has a rapidly rising prevalence in China. The patients,... (Review)
Review
Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) in western countries. Notably, it has a rapidly rising prevalence in China. The patients, commonly complicated with cardiovascular diseases and neurologic disorders, are at high risk to progress into end-stage renal disease (ESRD) and death. However, the pathogenic mechanisms of diabetic nephropathy have not been determined. Cellular senescence, which recently has gained broad attention, is thought to be an important player in the onset and development of diabetic nephropathy. In this issue, we generally review the mechanisms of cellular senescence in diabetic nephropathy, which involve telomere attrition, DNA damage, epigenetic alterations, mitochondrial dysfunction, loss of Klotho, Wnt/-catenin signaling activation, persistent inflammation, and accumulation of uremic toxins. Moreover, we highlight the potential therapeutic targets of cellular senescence in diabetic nephropathy and provide important clues for clinical strategies.
Topics: Animals; Cellular Senescence; DNA Damage; Diabetic Nephropathies; Epigenesis, Genetic; Humans; Mitophagy; Signal Transduction
PubMed: 31687085
DOI: 10.1155/2019/7495629 -
Cell Death & Disease Nov 2019Recent evidences indicate that signal transducer and activator of transcription 3 (STAT3) is one of the crucial signaling pathways in the progression of diabetic...
Recent evidences indicate that signal transducer and activator of transcription 3 (STAT3) is one of the crucial signaling pathways in the progression of diabetic nephropathy (DN). Here, we investigated the hypothesis that pharmacological blockade of STAT3 limits the progression of DN. Treatment with selective STAT3 inhibitor, S3I-201 for 16 weeks significantly attenuated kidney injuries in streptozotocin (STZ) induced diabetic mice, associated with downregulated expression of TGF-β1, ACE/AT1, and VEGF in diabetic mouse kidneys. Similar results were confirmed using genetic knockdown of STAT3 in mouse kidneys by injections of AAV2 expressing STAT3 shRNA in diabetic mouse. Further, STAT3 localization in kidney tissue was evaluated using immunofluorescent double-staining analysis, which indicated that STAT3 expression was mainly in the tubular epithelial cells. As expected, in renal tubular epithelial NRK-52E cells, high glucose (HG)-induced overexpression of TGF-β1, ACE/AT1, and VEGF were abrogated by S3I-201 pretreatment, as well as by genetic knockdown of STAT3 using specific siRNA sequence. This study found that renal tubular epithelial cells contributed to STAT3-mediated progression of DN and provided the first evidence that pharmacological inhibition of STAT3 attenuates DN.
Topics: Aminosalicylic Acids; Animals; Benzenesulfonates; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Fibrosis; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; STAT3 Transcription Factor
PubMed: 31699972
DOI: 10.1038/s41419-019-2085-0 -
Frontiers in Endocrinology 2022With the development of economy, the living standard of people all over the world has been greatly improved, and the incidence of diabetes is also increasing. Many...
BACKGROUND
With the development of economy, the living standard of people all over the world has been greatly improved, and the incidence of diabetes is also increasing. Many people with diabetes also develop other complications that reduce their quality of life. Diabetic nephropathy is a common complication of type2 diabetes. Understanding the related factors of diabetic nephropathy is greatly significant to control the occurrence of diabetic nephropathy and improve patient's life quality.
DATA AND METHODS
Data were collected from 2009 to 2018 in NHANES. Curve fitting graph was performed to investigate the association between globulin (GLB) and diabetic nephropathy(DN). Four logistic regression models were conducted to control the potential confounding factors. Subgroup analysis was carried out to assess the stability of results.
RESULTS
GLB was positively correlated with the occurrence of DN after controlling for potential confounders. Higher GLB was associated with an increased risk of diabetic nephropathy [odds ratio(OR), 1.10; 95% confidence interval (CI), 1.07-1.13, < 0.001].
CONCLUSIONS
In this cross-sectional study, GLB was significant positively correlated with the occurrence of DN in patients with type2 diabetes mellitus.
Topics: Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Globulins; Humans; Nutrition Surveys; Quality of Life
PubMed: 35898464
DOI: 10.3389/fendo.2022.890273 -
Medicine Oct 2023Diabetic nephropathy (DN) is a common and severe complication of diabetes mellitus and is the leading cause of chronic kidney disease (CKD) worldwide. Despite current... (Review)
Review
Diabetic nephropathy (DN) is a common and severe complication of diabetes mellitus and is the leading cause of chronic kidney disease (CKD) worldwide. Despite current treatments, many individuals with DN progress to end-stage renal disease (ESRD), requiring dialysis or kidney transplantation. The advancement in our understanding of the pathogenesis of diabetic nephropathy has led to the development of new prevention and treatment strategies. We comprehensively reviewed the literature on advances in the prevention and treatment of DN. We searched PubMed, Scopus, and Web of Science databases for articles published between 2000 and 2023, using keywords such as "diabetic nephropathy," "prevention," "treatment," and "recent advances." The recent advances in the prevention and treatment of DN include novel approaches targeting inflammation and fibrosis, such as inhibitors of the nuclear factor kappa-B (NF-kB) pathway, inhibitors of the transforming growth factor-beta (TGF-beta) pathway, and anti-inflammatory cytokines. Other promising strategies include stem cell therapy, gene therapy, and artificial intelligence-based approaches, such as predictive models based on machine learning algorithms that can identify individuals at high risk of developing DN and guide personalized treatment strategies. Combination therapies targeting multiple disease pathways may also offer the most significant potential for improving outcomes for individuals with DN. Overall, the recent advances in the prevention and treatment of DN represent promising avenues for future research and clinical development. Novel therapies targeting inflammation and fibrosis, stem cell and gene therapies, and artificial intelligence-based approaches all show great potential for improving outcomes for individuals with DN.
Topics: Humans; Diabetic Nephropathies; Artificial Intelligence; Renal Dialysis; Inflammation; Fibrosis; Kidney; Diabetes Mellitus
PubMed: 37800812
DOI: 10.1097/MD.0000000000035397 -
Frontiers in Endocrinology 2023A causal relationship concerning coffee intake and diabetic nephropathy (DN) is controversial. We conducted a Mendelian randomization study to assess the causal nature...
RATIONALE AND OBJECTIVE
A causal relationship concerning coffee intake and diabetic nephropathy (DN) is controversial. We conducted a Mendelian randomization study to assess the causal nature of these associations.
METHODS
40 independent single nucleotide polymorphisms (SNPs) associated with coffee intake were selected from the UK Biobank study. Summary-level data for diabetic nephropathy were obtained from publicly available genome-wide association studies (GWAS) and the FinnGen consortium. Inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods were used to examine a causal association. Sensitivity analyses included Cochran's Q test, the intercept of MR-Egger, MR-PRESSO, and the Outlier method. Leave-One-Out sensitivity analyses were also conducted to reduce the heterogeneity.
RESULTS
Our current study demonstrated positive associations of genetically predicted coffee intake with diabetic nephropathy (OR=1.939; = 0.045 and type 2 diabetes with renal complications (OR = 2.787, = 0.047). These findings were robust across several sensitivity analyses.
CONCLUSIONS
This study found a positive correlation between coffee consumption and the risk of diabetic nephropathy using genetic data. For a more accurate and trustworthy conclusion, subgroup analysis on coffee intake, including preparing method, variety of coffee, and quantity, is required.
Topics: Humans; Diabetic Nephropathies; Coffee; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Mendelian Randomization Analysis
PubMed: 37469984
DOI: 10.3389/fendo.2023.1169933 -
Stem Cell Research & Therapy Aug 2020Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the leading cause of end-stage chronic kidney disease. Currently, there are no...
BACKGROUND
Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the leading cause of end-stage chronic kidney disease. Currently, there are no effective drugs for treating DN. Therefore, novel and effective strategies to ameliorate DN at the early stage should be identified. This study aimed to explore the effectiveness and underlying mechanisms of human umbilical cord mesenchymal stem cells (UC-MSCs) in DN.
METHODS
We identified the basic biological properties and examined the multilineage differentiation potential of UC-MSCs. Streptozotocin (STZ)-induced DN rats were infused with 2 × 10 UC-MSCs via the tail vein at week 6. After 2 weeks, we measured blood glucose level, levels of renal function parameters in the blood and urine, and cytokine levels in the kidney and blood, and analyzed renal pathological changes after UC-MSC treatment. We also determined the colonization of UC-MSCs in the kidney with or without STZ injection. Moreover, in vitro experiments were performed to analyze cytokine levels of renal tubular epithelial cell lines (NRK-52E, HK2) and human renal glomerular endothelial cell line (hrGECs).
RESULTS
UC-MSCs significantly ameliorated functional parameters, such as 24-h urinary protein, creatinine clearance rate, serum creatinine, urea nitrogen, and renal hypertrophy index. Pathological changes in the kidney were manifested by significant reductions in renal vacuole degeneration, inflammatory cell infiltration, and renal interstitial fibrosis after UC-MSC treatment. We observed that the number of UC-MSCs recruited to the injured kidneys was increased compared with the controls. UC-MSCs apparently reduced the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and pro-fibrotic factor (TGF-β) in the kidney and blood of DN rats. In vitro experiments showed that UC-MSC conditioned medium and UC-MSC-derived exosomes decreased the production of these cytokines in high glucose-injured renal tubular epithelial cells, and renal glomerular endothelial cells. Moreover, UC-MSCs secreted large amounts of growth factors including epidermal growth factor, fibroblast growth factor, hepatocyte growth factor, and vascular endothelial growth factor.
CONCLUSION
UC-MSCs can effectively improve the renal function, inhibit inflammation and fibrosis, and prevent its progression in a model of diabetes-induced chronic renal injury, indicating that UC-MSCs could be a promising treatment strategy for DN.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelial Cells; Fibrosis; Humans; Inflammation; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pharmaceutical Preparations; Rats; Umbilical Cord; Vascular Endothelial Growth Factor A
PubMed: 32746936
DOI: 10.1186/s13287-020-01852-y -
Bioscience Reports Jun 2021The mechanisms underlying the therapeutic effect of Salvia miltiorrhiza (SM) on diabetic nephropathy (DN) were examined using a systematic network pharmacology approach...
The mechanisms underlying the therapeutic effect of Salvia miltiorrhiza (SM) on diabetic nephropathy (DN) were examined using a systematic network pharmacology approach and molecular docking. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of SM. Targets were obtained using the SwissTargetPrediction and TCMSP databases. Proteins related to DN were retrieved from the GeneCards and DisGeNET databases. A protein-protein interaction (PPI) network was constructed using common SM/DN targets in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The Metascape platform was used for Gene Ontology (GO) function analysis, and the Cytoscape plug-in ClueGO was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was performed using iGEMDOCK and AutoDock Vina software. Pymol and LigPlos were used for network mapping. Sixty-six active ingredients and 189 targets of SM were found. Sixty-four targets overlapped with DN-related proteins. The PPI network revealed that AKT serine/threonine kinase 1 (AKT1), VEGFA, interleukin 6 (IL6), TNF, mitogen-activated protein kinase 1 (MAPK1), tumor protein p53 (TP53), epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 14 (MAPK14), and JUN were the ten most relevant targets. GO and KEGG analyses revealed that the common targets of DN and SM were mainly involved in advanced glycation end-products, oxidative stress, inflammatory response, and immune regulation. Molecular docking revealed that potential DN-related targets, including tumor necrosis factor (TNF), NOS2, and AKT1, more stably bound with salvianolic acid B than with tanshinone IIA. In conclusion, the present study revealed the active components and potential molecular therapeutic mechanisms of SM in DN and provides a reference for the wide application of SM in clinically managing DN.
Topics: Animals; Databases, Genetic; Diabetic Nephropathies; Drugs, Chinese Herbal; Gene Expression Regulation; Gene Regulatory Networks; Humans; Molecular Docking Simulation; Network Pharmacology; Plant Extracts; Protein Interaction Maps; Salvia miltiorrhiza; Signal Transduction
PubMed: 33634308
DOI: 10.1042/BSR20203520 -
Nutrients Sep 2022Diabetic nephropathy (DN), a metabolic disease, is characterized by severe systemic metabolic disorders. A unique dietary pattern, such as intermittent fasting (IF) has... (Review)
Review
Diabetic nephropathy (DN), a metabolic disease, is characterized by severe systemic metabolic disorders. A unique dietary pattern, such as intermittent fasting (IF) has shown promising protective effects on various metabolic diseases, such as diabetes and cardiovascular and nervous system diseases. However, its role in regulating kidney disease, especially in DN, is still being investigated. Here, we summarize the current research progress, highlighting the relationship between IF and the risk factors for the progression of DN, and discuss the potential mechanisms by which IF improves renal injury in DN. Finally, we propose IF as a potential strategy to prevent and delay DN progression. Abbreviation: DN: Diabetic nephropathy; IF: Intermittent fasting; CPT1A: Carnitine palmitoyltransferase 1A; L-FABP: Liver-type fatty acid-binding protein; STZ: Streptozotocin; LDL: Low-density lipoproteins; HIIT: High-intensity interval training; CKD: Chronic kidney disease; ACEI: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin receptor blockers; MDA: Malondialdehyde; mtDNA: Mitochondrial DNA; UCP3: Uncoupling protein-3; MAM: Mitochondria-associated endoplasmic reticulum membrane; PBMCs: Peripheral blood mononuclear cells; ERK1/2: Extracellular signal-regulated kinase 1/2; DRP1: Dynamin-related protein 1; β-HB: β-Hydroxybutyrate; AcAc: Acetoacetate; GEO: Gene Expression Omnibus; NCBI: National Center for Biotechnology Information; mTORC1: Mechanistic target of rapamycin complex 1; HMGCS2: 3-Hydroxy-3-methylglutaryl-CoA synthase 2; GSK3β: Glycogen synthase kinase 3β; AKI: Acute kidney injury; CMA: Chaperone-mediated autophagy; FGF21: Fibroblast growth factor 21.
Topics: Diabetic Nephropathies; Fasting; Humans; Metabolic Diseases
PubMed: 36235648
DOI: 10.3390/nu14193995 -
Free Radical Biology & Medicine Jul 2022Diabetic nephropathy (DN) is known as a major microvascular complication in type 1 diabetes. The effect of insulin treatment alone on controlling blood glucose is...
Diabetic nephropathy (DN) is known as a major microvascular complication in type 1 diabetes. The effect of insulin treatment alone on controlling blood glucose is unsatisfactory. N-acetylcysteine (NAC), a chemical agent with thiol group, is found to confer a protective effect in renal injury. However, whether NAC combined with insulin treatment can further enhance the therapeutic effect in DN remains unclear. Here, we firstly used large mammal beagle as DN model to explore the effect of NAC combined with insulin treatment on DN during 120 d. Our results showed that NAC further alleviated mitochondrial oxidative damage and ferroptosis by enhancing activity of mitochondria GSH and maintaining mitochondrial redox homeostasis in DN. Additionally, the upregulated acetylation level of SOD2 was further abrogated by NAC treatment. In MDCK cells, NAC reduced high glucose (HG)-caused ferroptosis via activating Gpx4 expression. Of note, inhibition of Gpx4 by FIN56 abolished the protective effects of NAC on HG-induced ferroptosis. More importantly, 3-TYP reversed the effect of NAC on the mitochondria ROS under HG treatment, as well as eliminated its following beneficial effects for ferroptosis against HG-stimulated cells. These results reveal that NAC attenuated ferroptosis in DN via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2-Gpx4 signaling pathway.
Topics: Acetylcysteine; Animals; Diabetes Mellitus; Diabetic Nephropathies; Dogs; Ferroptosis; Homeostasis; Insulins; Mammals; Mitochondria; Oxidation-Reduction; Sirtuin 3
PubMed: 35660452
DOI: 10.1016/j.freeradbiomed.2022.05.024 -
Frontiers in Endocrinology 2022Diabetic nephropathy (DN) is regarded as the leading cause of end-stage renal disease worldwide and lacks novel therapeutic targets. To screen and verify special...
Diabetic nephropathy (DN) is regarded as the leading cause of end-stage renal disease worldwide and lacks novel therapeutic targets. To screen and verify special biomarkers for glomerular injury in patients with DN, fifteen datasets were retrieved from the Gene Expression Omnibus (GEO) database, correspondingly divided into training and testing cohorts and then merged. Using the limma package, 140 differentially expressed genes (DEGs) were screened out between 81 glomerular DN samples and 41 normal ones from the training cohort. With the help of the ConsensusClusterPlus and WGCNA packages, the 81 glomerular DN samples were distinctly divided into two subclusters, and two highly associated modules were identified. By using machine learning algorithms (LASSO, RF, and SVM-RFE) and the Venn diagram, two overlapping genes (PRKAR2B and TGFBI) were finally determined as potential biomarkers, which were further validated in external testing datasets and the HFD/STZ-induced mouse models. Based on the biomarkers, the diagnostic model was developed with reliable predictive ability for diabetic glomerular injury. Enrichment analyses indicated the apparent abnormal immune status in patients with DN, and the two biomarkers played an important role in the immune microenvironment. The identified biomarkers demonstrated a meaningful correlation between the immune cells' infiltration and renal function. In conclusion, two robust genes were identified as diagnostic biomarkers and may serve as potential targets for therapeutics of DN, which were closely associated with multiple immune cells.
Topics: Algorithms; Animals; Biomarkers; Diabetes Mellitus; Diabetic Nephropathies; Humans; Machine Learning; Mice
PubMed: 35663304
DOI: 10.3389/fendo.2022.876960