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1.
Front Endocrinol (Lausanne) ; 15: 1384953, 2024.
Article in English | MEDLINE | ID: mdl-38836233

ABSTRACT

Background: Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in kidney disease, yet its regulation in diabetic kidney disease (DKD) remains inadequately understood. Objective: Therefore, we investigated the changes of NAD+ levels in DKD and the underlying mechanism. Methods: Alternations of NAD+ levels and its biosynthesis enzymes were detected in kidneys from streptozotocin-induced diabetic mouse model by real-time PCR and immunoblot. The distribution of NAD+ de novo synthetic enzymes was explored via immunohistochemical study. NAD+ de novo synthetic metabolite was measured by LC-MS. Human data from NephroSeq were analyzed to verify our findings. Results: The study showed that NAD+ levels were decreased in diabetic kidneys. Both mRNA and protein levels of kynurenine 3-monooxygenase (KMO) in NAD+ de novo synthesis pathway were decreased, while NAD+ synthetic enzymes in salvage pathway and NAD+ consuming enzymes remained unchanged. Further analysis of human data suggested KMO, primarily expressed in the proximal tubules shown by our immunohistochemical staining, was consistently downregulated in human diabetic kidneys. Conclusion: Our study demonstrated KMO of NAD+ de novo synthesis pathway was decreased in diabetic kidney and might be responsible for NAD+ reduction in diabetic kidneys, offering valuable insights into complex regulatory mechanisms of NAD+ in DKD.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , NAD , Animals , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , NAD/metabolism , Humans , Mice , Diabetes Mellitus, Experimental/metabolism , Male , Mice, Inbred C57BL , Disease Models, Animal , Kidney/metabolism , Kidney/pathology
2.
J Cell Mol Med ; 28(11): e18364, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38837668

ABSTRACT

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.


Subject(s)
Diabetic Nephropathies , Kidney , Lipid Metabolism , Humans , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Animals , Kidney/metabolism , Kidney/pathology , Macrophages/metabolism , Cholesterol/metabolism , Fatty Acids/metabolism , Receptors, Immunologic/metabolism , Receptors, Immunologic/genetics , Oxysterols/metabolism , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
3.
BMC Med Genomics ; 17(1): 152, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38831322

ABSTRACT

OBJECTIVE: To investigate the role of BTG2 in periodontitis and diabetic kidney disease (DKD) and its potential underlying mechanism. METHODS: Gene expression data for periodontitis and DKD were acquired from the Gene Expression Omnibus (GEO) database. Differential expression analysis identified co-expressed genes between these conditions. The Nephroseq V5 online nephropathy database validated the role of these genes in DKD. Pearson correlation analysis identified genes associated with our target gene. We employed Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) networks to elucidate potential mechanisms. Expression levels of BTG2 mRNA were examined using quantitative polymerase Chain Reaction (qPCR) and immunofluorescence assays. Western blotting quantified proteins involved in epithelial-to-mesenchymal transition (EMT), apoptosis, mTORC1 signaling, and autophagy. Additionally, wound healing and flow cytometric apoptosis assays evaluated podocyte migration and apoptosis, respectively. RESULTS: Analysis of GEO database data revealed BTG2 as a commonly differentially expressed gene in both DKD and periodontitis. BTG2 expression was reduced in DKD compared to normal conditions and correlated with proteinuria. GSEA indicated enrichment of BTG2 in the EMT and mTORC1 signaling pathways. The PPI network highlighted BTG2's relevance to S100A9, S100A12, and FPR1. Immunofluorescence assays demonstrated significantly lower BTG2 expression in podocytes under high glucose (HG) conditions. Reduced BTG2 expression in HG-treated podocytes led to increased levels of EMT markers (α-SMA, vimentin) and the apoptotic protein Bim, alongside a decrease in nephrin. Lower BTG2 levels were associated with increased podocyte mobility and apoptosis, as well as elevated RPS6KB1 and mTOR levels, but reduced autophagy marker LC3. CONCLUSION: Our findings suggest that BTG2 is a crucial intermediary gene linking DKD and periodontitis. Modulating autophagy via inhibition of the mTORC1 signaling pathway, and consequently suppressing EMT, may be pivotal in the interplay between periodontitis and DKD.


Subject(s)
Apoptosis , Diabetic Nephropathies , Epithelial-Mesenchymal Transition , Periodontitis , Tumor Suppressor Proteins , Periodontitis/genetics , Periodontitis/metabolism , Periodontitis/pathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Humans , Tumor Suppressor Proteins/metabolism , Tumor Suppressor Proteins/genetics , Immediate-Early Proteins/metabolism , Immediate-Early Proteins/genetics , Podocytes/metabolism , Podocytes/pathology , Signal Transduction , Autophagy , Protein Interaction Maps , Mechanistic Target of Rapamycin Complex 1/metabolism , Cell Movement
4.
Ren Fail ; 46(2): 2359638, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38832484

ABSTRACT

Emerging data have revealed that damage to tubular epithelial cell is a driving force in the progression of diabetic kidney disease (DKD). However, the specific mechanisms by which lipotoxicity contributes to the injury of these cells, thereby influencing the development of DKD, are yet to be fully understood. Here, we analyzed the GSE 30529 microarray datasets of human tubulointerstitial tissue samples from the Gene Expression Omnibus database (GEO). Concurrently, we conducted RNA-sequencing on palmitic acid (PA)-treated human renal proximal tubule epithelial cells (HK2 cells). After normalization, the differentially expressed genes (DEGs) were screened by R software and gene ontology (GO) enrichment analysis was conducted, and lysosomal-associated protein transmembrane 5 (LAPTM5) was finally selected. Our findings indicate that the expression of LAPTM5 was obviously increased in DKD patients, and the correlation between LAPTM5, and other clinical parameters of DKD was analyzed using the Spearman correlation analysis. The potential of LAPTM5 as a prognostic biomarker for DKD was further consolidated through receiver operating characteristic (ROC) analysis. To further verify the function of LAPTM5, we established mouse or in vitro systems mimicking DKD. The results showed that a consistent upregulation of LAPTM5, which was also found to be linked with inflammatory mediators within the context of DKD. Additionally, LAPTM5 silencing significantly downregulated mRNA expression of inflammatory factors in PA-treated HK2 cells. These results indicate that LAPTM5 is a potential biomarker and therapeutic treatment target for DKD. This discovery paves the way for future research and development of targeted interventions aimed at mitigating the progression of this prevalent condition.


Subject(s)
Computational Biology , Diabetic Nephropathies , Membrane Proteins , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/genetics , Diabetic Nephropathies/etiology , Diabetic Nephropathies/pathology , Humans , Animals , Mice , Membrane Proteins/metabolism , Membrane Proteins/genetics , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Cell Line , Palmitic Acid/metabolism , Epithelial Cells/metabolism , Epithelial Cells/drug effects , Male , Mice, Inbred C57BL , Up-Regulation , Biomarkers/metabolism
5.
FASEB J ; 38(11): e23729, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38847786

ABSTRACT

Diabetic nephropathy (DN) is one of the common microvascular complications in diabetic patients. Marrow mesenchymal stem cells (MSCs) have attracted attention in DN therapy but the underlying mechanism remains unclear. Here, we show that MSC administration alleviates high glucose (HG)-induced human kidney tubular epithelial cell (HK-2 cell) injury and ameliorates renal injury in DN mice. We identify that Smad2/3 is responsible for MSCs-regulated DN progression. The activity of Smad2/3 was predominantly upregulated in HG-induced HK-2 cell and DN mice and suppressed with MSC administration. Activation of Smad2/3 via transforming growth factor-ß1 (TGF-ß1) administration abrogates the protective effect of MSCs on HG-induced HK-2 cell injury and renal injury of DN mice. Smad2/3 has been reported to interact with methyltransferase of N6-methyladenosine (m6A) complex and we found a methyltransferase, Wilms' tumor 1-associating protein (WTAP), is involved in MSCs-Smad2/3-regulated DN development. Moreover, WTAP overexpression abrogates the improvement of MSCs on HG-induced HK-2 cell injury and renal injury of DN mice. Subsequently, α-enolase (ENO1) is the downstream target of WTAP-mediated m6A modification and contributes to the MSCs-mediated regulation. Collectively, these findings reveal a molecular mechanism in DN progression and indicate that Smad2/3/WTAP/ENO1 may present a target for MSCs-mediated DN therapy.


Subject(s)
Diabetic Nephropathies , Mesenchymal Stem Cells , Smad2 Protein , Smad3 Protein , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Animals , Mesenchymal Stem Cells/metabolism , Smad2 Protein/metabolism , Mice , Humans , Smad3 Protein/metabolism , Male , Mice, Inbred C57BL , Adenosine/metabolism , Adenosine/analogs & derivatives , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Signal Transduction , Methyltransferases/metabolism , Methyltransferases/genetics , Mesenchymal Stem Cell Transplantation/methods , Transforming Growth Factor beta1/metabolism , Cell Line
6.
BMC Nephrol ; 25(1): 156, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38724923

ABSTRACT

BACKGROUND: Islet transplantation is an effective treatment for diabetes or even its complications. Aim of this study is to investigate efficacy of biomaterial treated islet transplantation on treating diabetic nephropathy. METHODS: Male rats were randomly divided into 6 groups; Control, diabetic control, diabetic transplanted with untreated islets, with platelet rich plasma treated islets, with pancreatic islets homogenate treated islets, or with these biomaterials combination treated islets. Islets cultured with biomaterials and transplanted to diabetic rats. After 60 days, biochemical, oxidative stress, and stereological parameters were assessed. RESULTS: Serum albumin and BUN concentration, decreased and increased respectively, Oxidative stress of kidney impaired, kidney weight, volume of kidney, cortex, medulla, glomerulus, proximal and distal tubules, collecting ducts, vessels, inflammatory, necrotic and fibrotic tissue in diabetic group increased compared to control group (p < 0.001). In treated groups, especially pancreatic islets homogenate treated islets transplanting animals, there was significant changes in kidney weight, and volume of kidney, proximal and distal tubules, Henle's loop and collecting ducts compared with diabetic group (p = 0.013 to p < 0.001). Combination treated islets animals showed significant increase in vessel volume compared to diabetic group (p < 0.001). Necrotic and fibrotic tissue significantly decreased in islets treated than untreated islet animals, it was higher in pancreatic islets homogenate, and combination treated islets groups (p = 0.001). CONCLUSIONS: Biomaterials treated islets transplanting could improve diabetic nephropathy. Improvement of oxidative stress followed by controlling glucose level, and effects of growth factors presenting in biomaterials can be considered as capable underlying mechanism of ameliorating inflammatory, necrotic and fibrotic tissue volume.


Subject(s)
Biocompatible Materials , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Islets of Langerhans Transplantation , Animals , Male , Rats , Diabetic Nephropathies/pathology , Islets of Langerhans Transplantation/methods , Biocompatible Materials/therapeutic use , Islets of Langerhans/pathology , Oxidative Stress , Rats, Sprague-Dawley , Treatment Outcome
7.
Sci Rep ; 14(1): 10344, 2024 05 06.
Article in English | MEDLINE | ID: mdl-38710706

ABSTRACT

Diabetic nephropathy (DN) is one of the most prevalent and severe complications of diabetes mellitus (DM) and is associated with increased morbidity and mortality. We aimed to investigate the associations between red, processed, and white meat consumption and the odds of developing kidney damage and DN in women. We enrolled 105 eligible women with DN and 105 controls (30-65 years). A validated and reliable food frequency questionnaire (FFQ) was used to evaluate the consumption of red, processed, and white meat. Biochemical variables and anthropometric measurements were assessed for all patients using pre-defined protocols. Binary logistic regression was conducted to examine possible associations. The results of the present study showed that there was a direct significant association between high consumption of red meat and processed meats and odds of microalbuminuria (red meat 2.30, 95% CI 1.25, 4.22; P-value = 0.007, processed meat: OR 2.16, 95% CI 1.18, 3.95; P-value = 0.01), severe albuminuria (red meat OR 3.25, 95% CI 1.38, 7.46; P-value = 0.007, processed meat: OR 2.35, 95% CI 1.01, 5.49; P-value = 0.04), BUN levels (red meat: OR 2.56, 95% CI 1.10, 5.93; P-value = 0.02, processed meat: OR 2.42, 95% CI 1.04, 5.62; P-value = 0.03), and DN (red meat 2.53, 95% CI 1.45, 4.42; P-value = 0.001, processed meat: OR 2.21; 95% CI 1.27, 3.85; P-value = 0.005). In summary, our study suggests that higher consumption of red and processed meat sources may be associated with microalbuminuria, severe albuminuria, higher BUN level, and higher odds of DN.


Subject(s)
Diabetic Nephropathies , Humans , Female , Middle Aged , Diabetic Nephropathies/etiology , Diabetic Nephropathies/pathology , Diabetic Nephropathies/epidemiology , Case-Control Studies , Adult , Aged , Albuminuria , Meat/adverse effects , Risk Factors , Red Meat/adverse effects , Meat Products/adverse effects
8.
FASEB J ; 38(10): e23668, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38742811

ABSTRACT

Podocyte injury plays a critical role in the progression of diabetic kidney disease (DKD), but the underlying cellular and molecular mechanisms remain poorly understanding. MicroRNAs (miRNAs) can disrupt gene expression by inducing translation inhibition and mRNA degradation, and recent evidence has shown that miRNAs may play a key role in many kidney diseases. In this study, we identified miR-4645-3p by global transcriptome expression profiling as one of the major downregulated miRNAs in high glucose-cultured podocytes. Moreover, whether DKD patients or STZ-induced diabetic mice, expression of miR-4645-3p was also significantly decreased in kidney. In the podocytes cultured by normal glucose, inhibition of miR-4645-3p expression promoted mitochondrial damage and podocyte apoptosis. In the podocytes cultured by high glucose (30 mM glucose), overexpression of miR-4645-3p significantly attenuated mitochondrial dysfunction and podocyte apoptosis induced by high glucose. Furthermore, we found that miR-4645-3p exerted protective roles by targeting Cdk5 inhibition. In vitro, miR-4645-3p obviously antagonized podocyte injury by inhibiting overexpression of Cdk5. In vivo of diabetic mice, podocyte injury, proteinuria, and impaired renal function were all effectively ameliorated by treatment with exogenous miR-4645-3p. Collectively, these findings demonstrate that miR-4645-3p can attenuate podocyte injury and mitochondrial dysfunction in DKD by targeting Cdk5. Sustaining the expression of miR-4645-3p in podocytes may be a novel strategy to treat DKD.


Subject(s)
Cyclin-Dependent Kinase 5 , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Mice, Inbred C57BL , MicroRNAs , Mitochondria , Podocytes , Podocytes/metabolism , Podocytes/pathology , Animals , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Mice , Mitochondria/metabolism , Male , Humans , Diabetes Mellitus, Experimental/metabolism , Cyclin-Dependent Kinase 5/metabolism , Cyclin-Dependent Kinase 5/genetics , Apoptosis , Glucose
9.
J Diabetes ; 16(6): e13565, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38751373

ABSTRACT

BACKGROUND: Diabetic nephropathy (DN) is a diabetic complication. LncRNAs are reported to participate in the pathophysiology of DN. Here, the function and mechanism of lncRNA small nucleolar RNA host gene 14 (SNHG14) in DN were explored. METHODS: Streptozotocin (STZ)-induced DN mouse models and high glucose (HG)-treated human mesangial cells (MCs) were used to detect SNHG14 expression. SNHG14 silencing plasmids were applied to examine the function of SNHG14 on proliferation and fibrosis in HG-treated MCs. Potential targets of SNHG14 were predicted using bioinformatics tools and verified by luciferase reporter, RNA pulldown, and northern blotting assays. The functional role of SNHG14 in DN in vivo was detected by injection with adenoviral vector carrying sh-SNHG14 into DN mice. Serum creatinine, blood urea nitrogen, blood glucose, 24-h proteinuria, relative kidney weight, and renal pathological changes were examined in DN mice. RESULTS: SNHG14 expression was elevated in the kidneys of DN mice and HG-treated MCs. SNHG14 silencing inhibited proliferation and fibrosis of HG-stimulated MCs. SNHG14 bound to miR-30e-5p to upregulate SOX4 expression. In rescue assays, SOX4 elevation diminished the effects of SNHG14 silencing in HG-treated MCs, and SOX4 silencing reversed the effects of SNHG14 overexpression. In in vivo studies, SNHG14 downregulation significantly ameliorated renal injuries and renal interstitial fibrosis in DN mice. CONCLUSIONS: SNHG14 silencing attenuates kidney injury in DN mice and reduces proliferation and fibrotic phenotype of HG-stimulated MCs via the miR-30e-5p/SOX4 axis.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , Disease Progression , MicroRNAs , RNA, Long Noncoding , SOXC Transcription Factors , Animals , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , RNA, Long Noncoding/genetics , SOXC Transcription Factors/genetics , SOXC Transcription Factors/metabolism , Mice , MicroRNAs/genetics , Humans , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/genetics , Male , Gene Silencing , Fibrosis , Cell Proliferation , Mesangial Cells/metabolism , Mesangial Cells/pathology , Mice, Inbred C57BL
10.
FASEB J ; 38(10): e23662, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38752545

ABSTRACT

The ubiquitination function in diabetic nephropathy (DN) has attracted much attention, but there is a lack of information on its ubiquitylome profile. To examine the differences in protein content and ubiquitination in the kidney between db/db mice and db/m mice, we deployed liquid chromatography-mass spectrometry (LC-MS/MS) to conduct analysis. We determined 145 sites in 86 upregulated modified proteins and 66 sites in 49 downregulated modified proteins at the ubiquitinated level. Moreover, 347 sites among the 319 modified proteins were present only in the db/db mouse kidneys, while 213 sites among the 199 modified proteins were present only in the db/m mouse kidneys. The subcellular localization study indicated that the cytoplasm had the highest proportion of ubiquitinated proteins (31.87%), followed by the nucleus (30.24%) and the plasma membrane (20.33%). The enrichment analysis revealed that the ubiquitinated proteins are mostly linked to tight junctions, oxidative phosphorylation, and thermogenesis. Podocin, as a typical protein of slit diaphragm, whose loss is a crucial cause of proteinuria in DN. Consistent with the results of ubiquitination omics, the K261R mutant of podocin induced the weakest ubiquitination compared with the K301R and K370R mutants. As an E3 ligase, c-Cbl binds to podocin, and the regulation of c-Cbl can impact the ubiquitination of podocin. In conclusion, in DN, podocin ubiquitination contributes to podocyte injury, and K261R is the most significant site. c-Cbl participates in podocin ubiquitination and may be a direct target for preserving the integrity of the slit diaphragm structure, hence reducing proteinuria in DN.


Subject(s)
Diabetic Nephropathies , Intracellular Signaling Peptides and Proteins , Membrane Proteins , Podocytes , Proto-Oncogene Proteins c-cbl , Ubiquitination , Animals , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Podocytes/metabolism , Podocytes/pathology , Mice , Proto-Oncogene Proteins c-cbl/metabolism , Proto-Oncogene Proteins c-cbl/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/metabolism , Membrane Proteins/genetics , Male , Mice, Inbred C57BL
11.
J Transl Med ; 22(1): 465, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755664

ABSTRACT

Disturbance in mitochondrial homeostasis within proximal tubules is a critical characteristic associated with diabetic kidney disease (DKD). CaMKKß/AMPK signaling plays an important role in regulating mitochondrial homeostasis. Despite the downregulation of CaMKKß in DKD pathology, the underlying mechanism remains elusive. The expression of NEDD4L, which is primarily localized to renal proximal tubules, is significantly upregulated in the renal tubules of mice with DKD. Coimmunoprecipitation (Co-IP) assays revealed a physical interaction between NEDD4L and CaMKKß. Moreover, deletion of NEDD4L under high glucose conditions prevented rapid CaMKKß protein degradation. In vitro studies revealed that the aberrant expression of NEDD4L negatively influences the protein stability of CaMKKß. This study also explored the role of NEDD4L in DKD by using AAV-shNedd4L in db/db mice. These findings confirmed that NEDD4L inhibition leads to a decrease in urine protein excretion, tubulointerstitial fibrosis, and oxidative stress, and mitochondrial dysfunction. Further in vitro studies demonstrated that si-Nedd4L suppressed mitochondrial fission and reactive oxygen species (ROS) production, effects antagonized by si-CaMKKß. In summary, the findings provided herein provide strong evidence that dysregulated NEDD4L disturbs mitochondrial homeostasis by negatively modulating CaMKKß in the context of DKD. This evidence underscores the potential of therapeutic interventions targeting NEDD4L and CaMKKß to safeguard renal tubular function in the management of DKD.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Kinase , Diabetic Nephropathies , Down-Regulation , Homeostasis , Mitochondria , Nedd4 Ubiquitin Protein Ligases , Animals , Nedd4 Ubiquitin Protein Ligases/metabolism , Nedd4 Ubiquitin Protein Ligases/genetics , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Mitochondria/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Mice, Inbred C57BL , Mice , Humans , Reactive Oxygen Species/metabolism , Male , Oxidative Stress , Mitochondrial Dynamics , Protein Stability , Proteolysis
12.
FASEB J ; 38(10): e23688, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38780519

ABSTRACT

Diabetic nephropathy (DN) is a major cause of chronic kidney disease. Microalbuminuria is currently the most common non-invasive biomarker for the early diagnosis of DN. However, renal structural damage may have advanced when albuminuria is detected. In this study, we sought biomarkers for early DN diagnosis through proteomic analysis of urinary extracellular vesicles (uEVs) from type 2 diabetic model rats and normal controls. Isocitrate dehydrogenase 1 (IDH1) was significantly increased in uEVs from diabetic model rats at the early stage despite minimal differences in albuminuria between the groups. Calorie restriction significantly suppressed the increase in IDH1 in uEVs and 24-hour urinary albumin excretion, suggesting that the increase in IDH1 in uEVs was associated with the progression of DN. Additionally, we investigated the origin of IDH1-containing uEVs based on their surface sugar chains. Lectin affinity enrichment and immunohistochemical staining showed that IDH1-containing uEVs were derived from proximal tubules. These findings suggest that the increase in IDH1 in uEVs reflects pathophysiological alterations in the proximal tubules and that IDH1 in uEVs may serve as a potential biomarker of DN in the proximal tubules.


Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Extracellular Vesicles , Isocitrate Dehydrogenase , Kidney Tubules, Proximal , Up-Regulation , Animals , Isocitrate Dehydrogenase/metabolism , Isocitrate Dehydrogenase/genetics , Extracellular Vesicles/metabolism , Rats , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Diabetes Mellitus, Type 2/urine , Diabetes Mellitus, Type 2/metabolism , Male , Diabetic Nephropathies/urine , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/urine , Rats, Sprague-Dawley , Biomarkers/urine , Biomarkers/metabolism
13.
Sci Rep ; 14(1): 11718, 2024 05 22.
Article in English | MEDLINE | ID: mdl-38778209

ABSTRACT

Protein misfolding in the endoplasmic reticulum (ER) of podocytes contributes to the pathogenesis of glomerular diseases. Protein misfolding activates the unfolded protein response (UPR), a compensatory signaling network. We address the role of the UPR and the UPR transducer, inositol-requiring enzyme 1α (IRE1α), in streptozotocin-induced diabetic nephropathy in mice. Diabetes caused progressive albuminuria in control mice that was exacerbated in podocyte-specific IRE1α knockout (KO) mice. Compared to diabetic controls, diabetic IRE1α KO mice showed reductions in podocyte number and synaptopodin. Glomerular ultrastructure was altered only in diabetic IRE1α KO mice; the major changes included widening of podocyte foot processes and glomerular basement membrane. Activation of the UPR and autophagy was evident in diabetic control, but not diabetic IRE1α KO mice. Analysis of human glomerular gene expression in the JuCKD-Glom database demonstrated induction of genes associated with the ER, UPR and autophagy in diabetic nephropathy. Thus, mice with podocyte-specific deletion of IRE1α demonstrate more severe diabetic nephropathy and attenuation of the glomerular UPR and autophagy, implying a protective effect of IRE1α. These results are consistent with data in human diabetic nephropathy and highlight the potential for therapeutically targeting these pathways.


Subject(s)
Autophagy , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Endoribonucleases , Mice, Knockout , Podocytes , Protein Serine-Threonine Kinases , Unfolded Protein Response , Animals , Podocytes/metabolism , Podocytes/pathology , Endoribonucleases/metabolism , Endoribonucleases/genetics , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Mice , Autophagy/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Humans , Male , Endoplasmic Reticulum Stress , Albuminuria/genetics , Albuminuria/metabolism , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Gene Deletion , Endoplasmic Reticulum/metabolism
14.
Cells ; 13(10)2024 May 16.
Article in English | MEDLINE | ID: mdl-38786068

ABSTRACT

Induction of the adenosine receptor A2B (A2BAR) expression in diabetic glomeruli correlates with an increased abundance of its endogenous ligand adenosine and the progression of kidney dysfunction. Remarkably, A2BAR antagonism protects from proteinuria in experimental diabetic nephropathy. We found that A2BAR antagonism preserves the arrangement of podocytes on the glomerular filtration barrier, reduces diabetes-induced focal adhesion kinase (FAK) activation, and attenuates podocyte foot processes effacement. In spreading assays using human podocytes in vitro, adenosine enhanced the rate of cell body expansion on laminin-coated glass and promoted peripheral pY397-FAK subcellular distribution, while selective A2BAR antagonism impeded these effects and attenuated the migratory capability of podocytes. Increased phosphorylation of the Myosin2A light chain accompanied the effects of adenosine. Furthermore, when the A2BAR was stimulated, the cells expanded more broadly and more staining of pS19 myosin was detected which co-localized with actin cables, suggesting increased contractility potential in cells planted onto a matrix with a stiffness similar to of the glomerular basement membrane. We conclude that A2BAR is involved in adhesion dynamics and contractile actin bundle formation, leading to podocyte foot processes effacement. The antagonism of this receptor may be an alternative to the intervention of glomerular barrier deterioration and proteinuria in the diabetic kidney disease.


Subject(s)
Cell Adhesion , Diabetes Mellitus, Experimental , Focal Adhesion Protein-Tyrosine Kinases , Podocytes , Proteinuria , Receptor, Adenosine A2B , Podocytes/metabolism , Podocytes/drug effects , Podocytes/pathology , Animals , Humans , Proteinuria/metabolism , Rats , Receptor, Adenosine A2B/metabolism , Cell Adhesion/drug effects , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Male , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/drug therapy , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine/metabolism , Adenosine/pharmacology , Cell Movement/drug effects , Phosphorylation/drug effects , Myosin Light Chains/metabolism
15.
Sci Rep ; 14(1): 11850, 2024 05 24.
Article in English | MEDLINE | ID: mdl-38782980

ABSTRACT

Natriuretic peptides (NPs) are cardio-derived hormones that have a crucial role in maintaining cardiovascular homeostasis. Physiological effects of NPs are mediated by binding to natriuretic peptide receptors 1 and 2 (NPR1/2), whereas natriuretic peptide receptor 3 (NPR3) acts as a clearance receptor that removes NPs from the circulation. Mouse studies have shown that local NP-signaling in the kidney glomerulus is important for the maintenance of renal homeostasis. In this study we examined the expression of NPR3 in kidney tissue and explored its involvement in renal physiology and disease by generating podocyte-specific knockout mice (NPR3podKO) as well as by using an NPR3 inhibitor (NPR3i) in rodent models of kidney disease. NPR3 was highly expressed by podocytes. NPR3podKO animals showed no renal abnormalities under healthy conditions and responded similarly to nephrotoxic serum (NTS) induced glomerular injury. However, NPR3i showed reno-protective effects in the NTS-induced model evidenced by decreased glomerulosclerosis and reduced podocyte loss. In a ZSF1 rat model of diabetic kidney injury, therapy alone with NPR3i did not have beneficial effects on renal function/histology, but when combined with losartan (angiotensin receptor blocker), NPR3i potentiated its ameliorative effects on albuminuria. In conclusion, these results suggest that NPR3 may contribute to kidney disease progression.


Subject(s)
Mice, Knockout , Podocytes , Receptors, Atrial Natriuretic Factor , Animals , Receptors, Atrial Natriuretic Factor/metabolism , Receptors, Atrial Natriuretic Factor/genetics , Mice , Podocytes/metabolism , Podocytes/pathology , Rats , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Male , Disease Models, Animal , Kidney Diseases/metabolism , Kidney Diseases/pathology , Losartan/pharmacology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology
16.
Cell Biochem Funct ; 42(4): e4037, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38736204

ABSTRACT

Diabetes mellitus is associated with secondary complications such as diabetic retinopathy (DR), nephropathy (DN), and cardiomyopathy (DCM), all of which significantly impact patient health. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory responses and endothelial dysfunction, both crucial in the pathogenesis of these complications. The goal of this review is to investigate at potential therapy methods that target ICAM-1 pathways and to better understand the multifaceted role of ICAM-1 in secondary diabetic problems. A meticulous analysis of scholarly literature published globally was conducted to examine ICAM-1involvement in inflammatory processes, endothelial dysfunction, and oxidative stress related to diabetes and its complications. Elevated ICAM-1 levels are strongly associated with augmented leukocyte adhesion, compromised microvascular function, and heightened oxidative stress in diabetes. These pathways contribute significantly to DR, DN, and DCM pathogenesis, highlighting ICAM-1 as a key player in their progression. Understanding ICAM-1 role in secondary diabetic complications offers insights into novel therapeutic strategies. Targeting ICAM-1 pathways may mitigate inflammation, improve endothelial function, and ultimately attenuate diabetic complications, thereby enhancing patient health outcomes. Continued research in this area is crucial for developing effective targeted therapies.


Subject(s)
Intercellular Adhesion Molecule-1 , Humans , Intercellular Adhesion Molecule-1/metabolism , Diabetes Complications/metabolism , Oxidative Stress , Animals , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Inflammation/metabolism , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/pathology , Diabetic Retinopathy/etiology
17.
BMC Nephrol ; 25(1): 172, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38769500

ABSTRACT

BACKGROUND: Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease and end-stage kidney disease. Its diverse range of manifestations complicates the treatment approach for patients. Although kidney biopsy is considered the gold standard for diagnosis, it lacks precision in predicting the progression of kidney dysfunction. Herein, we addressed whether the presence of glomerular crescents is linked to the outcomes in patients with biopsy-confirmed type 2 DKD. METHODS: We performed a retrospective evaluation, involving 327 patients diagnosed with biopsy-confirmed DKD in the context of type 2 diabetes, excluding cases with other glomerular diseases, from nine tertiary hospitals. Hazard ratios (HRs) were calculated using a Cox regression model to assess the risk of kidney disease progression, defined as either ≥ 50% decrease in estimated glomerular filtration rates or the development of end-stage kidney disease, based on the presence of glomerular crescents. RESULTS: Out of the 327 patients selected, ten patients had glomerular crescents observed in their biopsied tissues. Over the follow-up period (median of 19 months, with a maximum of 18 years), the crescent group exhibited a higher risk of kidney disease progression than the no crescent group, with an adjusted HR of 2.82 (1.32-6.06) (P = 0.008). The presence of heavy proteinuria was associated with an increased risk of developing glomerular crescents. CONCLUSION: The presence of glomerular crescents is indeed linked to the progression of type 2 DKD. Therefore, it is important to determine whether there is an additional immune-mediated glomerulonephritis requiring immunomodulation, and it may be prudent to monitor the histology and repeat a biopsy.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Disease Progression , Kidney Glomerulus , Humans , Diabetic Nephropathies/pathology , Retrospective Studies , Male , Female , Middle Aged , Diabetes Mellitus, Type 2/complications , Kidney Glomerulus/pathology , Aged , Glomerular Filtration Rate , Cohort Studies , Biopsy , Kidney Failure, Chronic , Risk Factors
18.
Diabetes Metab Res Rev ; 40(4): e3809, 2024 May.
Article in English | MEDLINE | ID: mdl-38708843

ABSTRACT

Diabetic kidney disease (DKD), one of the common microvascular complications of diabetes, is increasing in prevalence worldwide and can lead to End-stage renal disease. However, there are still gaps in our understanding of the pathophysiology of DKD, and both current clinical diagnostic methods and treatment strategies have drawbacks. According to recent research, long non-coding RNAs (lncRNAs) are intimately linked to the developmental process of DKD and could be viable targets for clinical diagnostic decisions and therapeutic interventions. Here, we review recent insights gained into lncRNAs in pathological changes of DKD such as mesangial expansion, podocyte injury, renal tubular injury, and interstitial fibrosis. We also discuss the clinical applications of DKD-associated lncRNAs as diagnostic biomarkers and therapeutic targets, as well as their limitations and challenges, to provide new methods for the prevention, diagnosis, and treatment of DKD.


Subject(s)
Diabetic Nephropathies , RNA, Long Noncoding , Humans , Diabetic Nephropathies/pathology , Diabetic Nephropathies/etiology , Diabetic Nephropathies/genetics , RNA, Long Noncoding/physiology , RNA, Long Noncoding/genetics , Biomarkers/analysis , Animals , Podocytes/pathology , Podocytes/metabolism
19.
Life Sci ; 349: 122722, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38754814

ABSTRACT

AIMS: Steroidogenic acute regulatory (StAR)-related lipid transfer domain-3 (STARD3) is a sterol-binding protein that facilitates cholesterol transport between cellular organelles. Cholesterol accumulation in podocytes directly contributes to the pathogenesis of albuminuria and renal injury under the condition of diabetic kidney disease (DKD). The aim of this study is to determine the role of STARD3 on the intracellular distribution of cholesterol within podocytes. METHODS: In vivo and in vitro models of diabetes were performed. The protein levels of STARD3, Niemann-Pick disease type C1 (NPC1), and Niemann-Pick disease type C2 (NPC2) were respectively detected by western blot analysis, immunohistochemistry, and immunofluorescence. Filipin staining was used to evaluate the subcellular localization of cholesterol in podocytes. Mitochondrial damage was evaluated using JC-1 (CBIC2) and ROS (reactive oxygen species) assays. KEY FINDINGS: Upregulation of STARD3 under diabetes and hyperglycemia increases cholesterol transport from the late endosomal/lysosomal (LE/LY) to mitochondria, leading to mitochondrial cholesterol accumulation and cell injury in podocytes. Conversely, downregulating STARD3 expression attenuated mitochondrial cholesterol accumulation, and improved mitochondrial homeostasis. SIGNIFICANCE: STARD3 may govern intracellular cholesterol transport in podocytes, subsequently leading to regulation of mitochondrial metabolism. Therefore, targeting STARD3 emerges as a potential therapeutic strategy to mitigate diabetes-induced mitochondrial cholesterol accumulation and associated injury in podocytes.


Subject(s)
Cholesterol , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Mitochondria , Podocytes , Podocytes/metabolism , Podocytes/pathology , Animals , Cholesterol/metabolism , Mitochondria/metabolism , Mice , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Male , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Biological Transport , Mice, Inbred C57BL , Humans
20.
Kidney Int ; 105(6): 1157-1159, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38777398

ABSTRACT

Chen et al. identify dysregulation of the transcriptional activator Yes-associated protein in the podocytes of diabetic mouse and human kidneys. Podocyte Yes-associated protein deficiency led to downregulation of the key transcription factor Wilms' tumor 1, and worsened podocyte injury in a mouse model of diabetic kidney injury. Yes-associated protein may therefore play a critical role in diabetic podocyte injury via regulation of Wilms' tumor 1 expression.


Subject(s)
Adaptor Proteins, Signal Transducing , Diabetic Nephropathies , Podocytes , Transcription Factors , WT1 Proteins , YAP-Signaling Proteins , Podocytes/metabolism , Podocytes/pathology , Animals , Humans , YAP-Signaling Proteins/metabolism , Transcription Factors/metabolism , Transcription Factors/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , WT1 Proteins/metabolism , WT1 Proteins/genetics , Mice , Diabetic Nephropathies/pathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/etiology , Phosphoproteins/metabolism , Phosphoproteins/genetics , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics
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