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Urinary exosome proteins PAK6 and EGFR as noninvasive diagnostic biomarkers of diabetic nephropathy.BMC Nephrology Oct 2023The actin cytoskeleton plays an essential role in maintaining podocyte functions. However, whether the urinary exosome proteins related to the regulation of the actin...
OBJECTIVE
The actin cytoskeleton plays an essential role in maintaining podocyte functions. However, whether the urinary exosome proteins related to the regulation of the actin cytoskeleton are changed in diabetic nephropathy (DN) is still unknown. This study was to investigate the possibility that related proteins can be applied as diagnostic biomarkers for DN.
METHODS
Urinary exosomes were obtained from 144 participants (Discovery phase: n = 72; Validation phase: n = 72) by size exclusion chromatography methods. Proteomic analysis of urinary exosome by LC-MS/MS. Western blot and ELISA were applied to validate the selected urinary exosome proteins. The clinical value of selected urinary exosome proteins was evaluated using correlation and receiver operating characteristic curve analyses.
RESULTS
Fifteen urinary proteins related to the regulation of the actin cytoskeleton were identified in urinary exosomes. Three upregulated proteins were selected, including Serine/threonine-protein kinase PAK6 (PAK6), Epidermal growth factor receptor (EGFR), and SHC-transforming protein 1(SHC1). The expression level of PAK6 and EGFR was negatively correlated with estimated glomerular filtration rate and positively correlated with serum creatinine levels. For diagnosing DN in the discovery phase: the area under curve (AUC) of PAK6 was 0.903, EGFR was 0.842, and the combination of two proteins was 0.912. These better performances were also observed in the validation phase (For PAK6: AUC = 0.829; For EGFR: AUC = 0.797; For PAK6 + EGFR: AUC = 0.897).
CONCLUSIONS
Urinary exosome proteins PAK6 and EGFR may be promising and noninvasive biomarkers for diagnosing DN.
Topics: Humans; Diabetic Nephropathies; Exosomes; Proteomics; Chromatography, Liquid; Tandem Mass Spectrometry; Proteins; Biomarkers; ErbB Receptors; Diabetes Mellitus, Type 2; p21-Activated Kinases
PubMed: 37789280
DOI: 10.1186/s12882-023-03343-7 -
Journal of Translational Medicine Oct 2023Whether serum vitamin D mediate vascular diseases in prediabetic populations remains unclear. This study aimed to determine the associations between circulating...
BACKGROUND
Whether serum vitamin D mediate vascular diseases in prediabetic populations remains unclear. This study aimed to determine the associations between circulating 25-hydroxyvitamin D [25(OH)D] levels and vitamin D receptor (VDR) polymorphisms with the risk of macrovascular complications, including myocardial infarction and stroke, and microvascular complications such as diabetic nephropathy and retinopathy, among adults with prediabetes.
METHODS
Participants with prediabetes in UK Biobank were included (N = 56,387). Multivariable dose-response and Cox proportion models were used to explore the relationship of serum 25(OH)D status and the risks of vascular complications. The interaction of VDR polymorphisms with serum 25(OH)D level on risks of vascular events was also assessed.
RESULTS
During a median follow-up of 12 years, higher levels of 25(OH)D were significantly and nonlinearly associated with a lower risk of macrovascular diseases among prediabetic individuals. The adjusted hazard ratios (95% confidential interval) of serum 25(OH)D levels of ≥ 75.0 nmol/L versus < 25 nmol/L were 0.75 (0.63-0.88) for myocardial infarction, 0.74 (0.55-1.00) for stroke, 1.02 (0.60-1.74) for diabetic nephropathy, and 1.30 (0.92-1.84) for diabetic retinopathy, respectively. The rs2228570 (FokI) polymorphisms significantly interacted with 25(OH)D on incident myocardial infarction (P-interaction = 0.042) and stroke (P-interaction = 0.033). The individuals with serum 25(OH)D level of 50.0-74.9 nmol/L and rs2228570 (FokI) homozygotes had the lowest risks of vascular complications.
CONCLUSIONS
Lower serum 25(OH)D levels are significantly and nonlinearly associated with an increased risk of cardiocerebrovascular diseases in prediabetic individuals, with VDR polymorphisms of rs2228570 (FokI) modify such associations. Monitoring a safe 25(OH)D concentration is suggested to prevent the vascular complications for prediabetes.
Topics: Adult; Humans; Prospective Studies; Prediabetic State; Diabetic Nephropathies; Vitamin D; Myocardial Infarction; Stroke; Vitamin D Deficiency
PubMed: 37845735
DOI: 10.1186/s12967-023-04557-x -
The Journal of Biological Chemistry Sep 2023A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease...
A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. Because of the critical role of ChREBP in lipid metabolism, we interrogated whether and how mitochondrial lipidomes play a role in ChREBP-mediated mitochondrial fission. Our findings suggest a key role for a family of ether phospholipids in ChREBP-induced mitochondrial remodeling. We find that overexpression of glyceronephosphate O-acyltransferase, a critical enzyme in the biosynthesis of plasmalogens, reverses the protective phenotype of ChREBP deficiency on mitochondrial fragmentation. Finally, our data also points to Gnpat as a direct transcriptional target of ChREBP. Taken together, our results uncover a distinct mitochondrial lipid signature as the link between ChREBP-induced mitochondrial dynamics and progression of DKD.
Topics: Animals; Mice; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Diabetes Mellitus; Diabetic Nephropathies; Gene Expression Regulation; Kidney; Lipidomics; Transcription Factors
PubMed: 37611830
DOI: 10.1016/j.jbc.2023.105185 -
Iranian Journal of Kidney Diseases Nov 2023\Introduction. Diabetes mellitus (DM) is one of the most common chronic diseases worldwide, and diabetic nephropathy (DN) is the most significant complication of DM,...
UNLABELLED
\Introduction. Diabetes mellitus (DM) is one of the most common chronic diseases worldwide, and diabetic nephropathy (DN) is the most significant complication of DM, which is highly prevalent and difficult to cure. This research project aims to investigate the role and mechanism of Nucleoporin 160kDa (NUP160)-regulated autophagy in the pathogenesis of DN.
METHODS
NUP160 levels in diabetic and non-diabetic kidney tissues were measured by Western blot, and the connection between NUP160 and renal function of DN patients was analyzed. The podocytes were divided into four groups, namely the standard group (culture medium: standard glucose solution), high glucose (HG) group (HG solution), HG+si-NUP160 group (HG solution+si-NUP160 transfection) and HG+si-NC group (HG solution+si-NUP 160 transfection) for the determination of apoptosis by flow cytometry and measurements of LC3B, Prostacyclin-62 (P62), Janus kinase 2 (JAK2) and Signal transducer and activator of transcription3 (STAT3) by Western blot.
RESULTS
In DN patients, NUP160 decreased in podocytes and was inversely proportional to Blood urea nitrogen (BUN), Serum creatinine (Scr) and β2-Microglobulin (β2-MG) (P < .05). Compared with a standard group, the apoptosis rate, P62 level, and the ratios of phosphorylation-JAK2 (p-JAK2)/JAK2, phosphorylation-STAT3 (p-STAT3)/STAT3, and LC3B-Ⅱ/LC3B-Ⅰ elevated in the other three groups (P < .05). Apoptosis rate and P62 level, p-JAK2/JAK2 and p-STAT3/STAT3 ratios increased, and LC3B-Ⅱ/LC3B-Ⅰ ratio decreased in the HG+si-NUP160 group (P < .05), while those in HG+si-NC group showed no evident changes, compared with HG group (P > .05).
CONCLUSION
NUP160 is downregulated in DN and can affect cellular autophagy through the activation of JAK2/STAT3 signaling pathway. DOI: 10.52547/ijkd.7884.
Topics: Humans; Diabetic Nephropathies; Podocytes; Signal Transduction; Glucose; Autophagy; Apoptosis; Diabetes Mellitus; Nuclear Pore Complex Proteins
PubMed: 38043110
DOI: No ID Found -
Drug Design, Development and Therapy 2023Diabetic nephropathy (DN), as a chronic inflammatory complication of diabetes, is characterized by hyperglycemia, albuminuria and edema, which ultimately becomes the...
BACKGROUND
Diabetic nephropathy (DN), as a chronic inflammatory complication of diabetes, is characterized by hyperglycemia, albuminuria and edema, which ultimately becomes the leading cause of end-stage renal disease (ESRD). Astragalus polysaccharide (APS), extracted from the , was widely used in the treatment of diabetes mellitus. However, the functional roles of APS ameliorate inflammatory responses in DN, which remain poorly understood. Therefore, the purpose of this study was to explore the molecular mechanism of APS on DN in vivo and vitro models.
METHODS
We explored the beneficial effects of APS in streptozotocin (STZ)-induced DN rat model and high glucose (HG)-treated glomerular podocyte model. The fasting blood glucose (FBG) and ratio of kidney weight to body weight were measured after 4 weeks of APS treatment. The renal injury parameters containing serum creatinine (Scr), blood urea nitrogen (BUN) and 24 h urinary protein were evaluated. The renal pathological examination was observed by hematoxylin-eosin (HE) staining. The levels of IL-1β, IL-6 and MCP-1 were evaluated by ELISA assay. The proliferation of podocytes was determined using CCK-8 assay and flow cytometry. qRT-PCR and Western blot analysis were performed to determine the amounts of TLR4/NF-κB-related gene expression.
RESULTS
Our results indicated that APS effectively decreased the levels of FBG, BUN, Scr and renal pathological damage when compared with STZ-induced DN model group. Additionally, APS significantly ameliorated renal injury by reducing inflammatory cytokines IL-1β, IL-6, MCP-1 expression and inhibiting the TLR4/NF-κB pathway activity in DN rats. Consistent with the results in vitro, the HG-induced inflammatory response and proliferation of glomerular podocytes were also alleviated through APS administration.
CONCLUSION
We found that APS ameliorated DN renal injury, and the mechanisms perhaps related to relieving inflammatory responses and attenuating the TLR4/NF-κB signaling pathway.
Topics: Animals; Rats; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Interleukin-6; Kidney; NF-kappa B; Polysaccharides; Rats, Sprague-Dawley; Streptozocin; Toll-Like Receptor 4; Astragalus Plant
PubMed: 37489175
DOI: 10.2147/DDDT.S411211 -
Clinical and Experimental Nephrology Jul 2024The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects... (Review)
Review
The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.
Topics: Animals; Humans; Albuminuria; Claudin-1; Cytokines; Diabetic Nephropathies; Epigenesis, Genetic; Fibrosis; Kidney Tubules, Proximal; Mice, Inbred C57BL; Mice, Knockout; NAD; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Podocytes; Sirtuin 1; Sirtuins; Tissue Inhibitor of Metalloproteinase-1
PubMed: 38587753
DOI: 10.1007/s10157-024-02502-w -
Computers in Biology and Medicine Nov 2023Diabetic nephropathy (DN) is a common systemic microvascular complication of diabetes and a leading cause of chronic kidney disease worldwide. Urinary extracellular...
BACKGROUND
Diabetic nephropathy (DN) is a common systemic microvascular complication of diabetes and a leading cause of chronic kidney disease worldwide. Urinary extracellular vesicles (uEVs), which are natural nanoscale vesicles that protect RNA from degradation, have the potential to serve as an invasive diagnostic biomarker for DN.
METHODS
We enrolled 24 participants, including twelve with renal biopsy-proven TDN and twelve with TDM, and isolated uEVs using ultracentrifugation. We performed microarrays for mRNAs, lncRNAs, and circRNAs in parallel, and Next-Generation Sequencing for miRNAs. Differentially expressed RNAs (DE-RNAs) were subjected to CIBERSORTx, ssGSEA analysis, GO enrichment, PPI network analysis, and construction of the lncRNA/circRNA-miRNA-mRNA regulatory network. Candidate genes and potential biomarker RNAs were validated using databases and machine learning models.
RESULTS
A total of 1684 mRNAs, 126 lncRNAs, 123 circRNAs and 66 miRNAs were found in uEVs in TDN samples compared with TDM. CIBERSORTx revealed the involvement of uEVs in immune activity and ssGSEA explored possible cell or tissue sources of uEVs. A ceRNA co-expression and regulation relationship network was constructed. Candidate genes MYO1C and SP100 mRNA were confirmed to be expressed in the kidney using Nephroseq database, scRNA-seq dataset, and Human Protein Atlas database. We further selected 2 circRNAs, 2 miRNAs, and 2 lncRNAs from WGCNAs and ceRNAs and demonstrated their efficacy as potential diagnostic biomarkers for TDN using machine learning algorithms.
CONCLUSIONS
This study reported, for the first time, the whole-transcriptome genetic resources found in urine extracellular vesicles of TDN patients. The results provide additional support for the possible interactions, and regulators between RNAs from uEVs themselves and as potential biomarkers in DN.
Topics: Humans; Diabetic Nephropathies; Extracellular Vesicles; Male; Gene Expression Profiling; Middle Aged; Female; Transcriptome; Biomarkers; MicroRNAs; RNA, Circular; RNA, Messenger; Diabetes Mellitus, Type 2; Gene Regulatory Networks; RNA, Long Noncoding
PubMed: 37738894
DOI: 10.1016/j.compbiomed.2023.107480 -
Frontiers in Endocrinology 2023The pathogenesis of diabetic nephropathy (DN) is complex, inflammation is the central link among the inducing factors in the existing research, and the gutkidney axis...
INTRODUCTION
The pathogenesis of diabetic nephropathy (DN) is complex, inflammation is the central link among the inducing factors in the existing research, and the gutkidney axis could scientifically explain the reasons for the accumulation of chronic low-grade inflammation. As both a medicine and food, corn silk contains abundant polysaccharides. Historical studies and modern research have both confirmed its intervention effect on diabetes and DN, but the mechanism of action is unclear.
METHODS
In this study, a DN rat model was generated, and the therapeutic effect of corn silk polysaccharides (CSPs) was evaluated based on behavioral, histopathological and biochemical indicators. We attempted to fully understand the interactions between CSPs, the gut microbiota and the host at the systemic level from a gut microbiota metabolomics perspective to fundamentally elucidate the mechanisms of action that can be used to intervene in DN.
RESULTS
Research has found that the metabolic pathways with a strong correlation with CSPs were initially identified as glycerophosphate, fatty acid, bile acid, tyrosine, tryptophan and phenylalanine metabolism and involved Firmicutes, Bacteroides, Lachnospiraceae-NK4A136- group and Dubosiella, suggesting that the effect of CSPs on improving DN is related to changes in metabolite profiles and gut microbiota characteristics.
DISCUSSION
CSPs could be harnessed to treat the abnormal metabolism of endogenous substances such as bile acids and uremic toxins caused by changes in gut microbiota, thus alleviating kidney damage caused by inflammation. In view of its natural abundance, corn silk is safe and nontoxic and can be used for the prevention and treatment of diabetes and DN.
Topics: Rats; Animals; Diabetic Nephropathies; Zea mays; Gastrointestinal Microbiome; Ecosystem; Inflammation; Homeostasis; Polysaccharides; Silk; Diabetes Mellitus
PubMed: 38111708
DOI: 10.3389/fendo.2023.1232132 -
Biomedicine & Pharmacotherapy =... Dec 2023Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2)...
Central administration of Dapagliflozin alleviates a hypothalamic neuroinflammatory signature and changing tubular lipid metabolism in type 2 diabetic nephropathy by upregulating MCPIP1.
BACKGROUND
Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD).
METHODS
Blood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet, db/db mice and palmitic acid (PA)-stimulated BV2 microglia were used for study models. 0.28 mg/3ul dapagliflozin was injected into the lateral ventricle in db/db mice. Genes and protein expression levels were determined by qPCR, western blotting, immunofluorescence, and immunohistochemistry staining. Secreted IL-1β and IL-6 were quantified by ELISA. Oil red O staining, lipidomic, and non-targeted metabolomics were performed to evaluate abnormal lipid metabolism in kidney.
RESULTS
The decrease of serum MCPIP1 was an independent risk factor for renal progression in DKD patients (OR=1.22, 95 %CI: 1.02-1.45, P = 0.033). Higher microglia marker IBA1 and lower MCPIP1 in the hypothalamus, as well as lipid droplet deposition increasing in the kidney were observed in DKD rats. Central dapagliflozin could reduce the blood sugar, hypothalamic inflammatory cytokines, lipid droplet deposition in renal tubular. Lipidomics and metabolomics results showed that dapagliflozin changed 37 lipids and 19 metabolites considered on promoting lipolysis. These lipid metabolism changes were attributed to dapagliflozin by upregulating MCPIP1, and inhibiting cytokines in the microglia induced by PA.
CONCLUSIONS
Central administrated Dapagliflozin elicits an anti-inflammatory effect by upregulating MCPIP1 levels in microglia and changes lipid metabolism in kidney of DKD.
Topics: Humans; Mice; Male; Rats; Animals; Diabetic Nephropathies; Neuroinflammatory Diseases; Lipid Metabolism; Rats, Sprague-Dawley; Kidney; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Cytokines
PubMed: 37931516
DOI: 10.1016/j.biopha.2023.115840 -
Frontiers in Immunology 2023Podocyte injury, which involves the podocyte epithelial-mesenchymal transition (EMT) process, is a crucial factor contributing to the progression of diabetic nephropathy...
BACKGROUND
Podocyte injury, which involves the podocyte epithelial-mesenchymal transition (EMT) process, is a crucial factor contributing to the progression of diabetic nephropathy (DN) and proteinuria. Our study aimed to examine the protective properties of Angiopoietin-like protein 3 (Angptl3) knockout on podocyte damage and macrophage polarization in DN mice and podocytes treated with HG. Furthermore, we also sought to investigate the underlying molecular mechanism responsible for these effects.
METHODS
DN was induced in B6;129S5 mice through intraperitoneal injection of 40 mg/kg of streptozotocin (STZ). Subsequently, the changes in renal function, podocyte apoptosis, inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]), IL-10, TGF-β1, IL-1Ra, IL-10Ra, and nephrin were evaluated. Moreover, we investigated the mechanism underlying the role of Angptl3 in macrophages polarization, podocyte injury, podocyte EMT.
RESULTS
Our findings revealed that Angptl3 knockout significantly attenuated STZ or HG-induced renal dysfunction and podocyte EMT. In both and studies, Angptl3 knockout led to (1) promote the transformation of M1 type macrophages into M2 type macrophages; (2) amelioration of the reduced expression of nephrin, synaptopodin, and podocin; (3) inhibition of NLRP3 inflammasome activation and release of IL-1β; and (4) regulation of α-SMA expression via the macrophage polarization. (5) After HG treatment, there was an increase in pro-inflammatory factors and foot cell damage. These changes were reversed upon Angptle knockdown.
CONCLUSION
Our study suggests that the knockout of Angptl3 alleviates podocyte EMT and podocyte injury by regulating macrophage polarization.
Topics: Animals; Mice; Angiopoietin-Like Protein 3; Apoptosis; Diabetes Mellitus; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Podocytes
PubMed: 37638046
DOI: 10.3389/fimmu.2023.1228399