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Cell Biology and Toxicology Jun 2024Long noncoding RNAs play an important role in several pathogenic processes in diabetic nephropathy, but the relationship with epithelial-mesenchymal transition in DN is...
Long noncoding RNAs play an important role in several pathogenic processes in diabetic nephropathy, but the relationship with epithelial-mesenchymal transition in DN is unclear. Herein, we found that KIFAP3-5:1 expression was significantly down-regulated in DN plasma samples, db/db mouse kidney tissues and high glucose treated renal tubular epithelial cells compared to normal healthy samples and untreated cells. Overexpression of KIFAP3-5:1 improved renal fibrosis in db/db mice and rescued epithelial-mesenchymal transition of high glucose cultured renal tubular epithelial cells. The silence of KIFAP3-5:1 will exacerbate the progression of EMT. Mechanistically, KIFAP3-5:1 was confirmed to directly target to the -488 to -609 element of the PRRX1 promoter and negatively modulate PRRX1 mRNA and protein expressions. Furthermore, rescue assays demonstrated that the knockdown of PRRX1 counteracted the KIFAP3-5:1 low expression-mediated effects on EMT in hRPTECs cultured under high glucose. The plasma KIFAP3-5:1 of DN patients is highly correlated with the severity of renal dysfunction and plays an important role in the prediction model of DN diseases. These findings suggested that KIFAP3-5:1 plays a critical role in regulation of renal EMT and fibrosis through suppress PRRX1, and highlight the clinical potential of KIFAP3-5:1 to assist in the diagnosis of diabetic nephropathy.
Topics: Epithelial-Mesenchymal Transition; Diabetic Nephropathies; RNA, Long Noncoding; Animals; Humans; Mice; Kidney Tubules; Homeodomain Proteins; Male; Epithelial Cells; Glucose; Fibrosis; Mice, Inbred C57BL; Female; Middle Aged
PubMed: 38869718
DOI: 10.1007/s10565-024-09874-5 -
Open Forum Infectious Diseases Jun 2024Foot complications are common in people with diabetes mellitus (DM), leading to increased health care utilization, heightened mortality risk, and notable recurrence...
BACKGROUND
Foot complications are common in people with diabetes mellitus (DM), leading to increased health care utilization, heightened mortality risk, and notable recurrence rates even after treatment. This retrospective cohort study aimed to investigate the impact of repeated occurrence of DM-related foot complications on the risk of all-cause mortality and to identify the potential risk factors associated with repeated events.
METHODS
People with DM admitted with foot complications (ulcer, skin and soft tissue infection, or osteomyelitis) from 2012 to 2014 were identified from Taiwan's National Health Insurance Research Database, with a 3-year follow-up for repeated events. We categorized the study subjects based on their cumulative number of hospital admissions with foot complications. Logistic regression was conducted to explore the potential risk factors associated with repeated diabetic foot events. Kaplan-Meier curves and Cox proportional hazard models were used to examine the associations between repeated diabetic foot events and all-cause mortality.
RESULTS
In this study, 28 754 eligible individuals were enrolled and classified into 3 groups: no repeated diabetic foot events (76.1%), 1 repeated event (16.0%), and 2 or more repeated events (7.9%). Logistic regression revealed that advanced age, male sex, congestive heart failure, dyslipidemia, hypertension, nephropathy, retinopathy, neuropathy, peripheral vascular disease, diabetes-related preventable hospitalizations, and outpatient visits due to diabetic foot were significantly associated with repeated events of diabetic foot complications. Compared with those with no repeated events, the adjusted hazard ratios for all-cause mortality were 1.26 (95% CI, 1.19-1.34) for 1 repeated event and 1.36 (95% CI, 1.26-1.47) for 2 or more repeated events.
CONCLUSIONS
The significant association between repeated diabetic foot and elevated mortality risk highlights the critical necessity for proactive and targeted patient care within clinical practice. More research to delve into the predictive factors related to the repeated occurrence of diabetic foot is needed to provide additional insights for prevention strategies.
PubMed: 38868313
DOI: 10.1093/ofid/ofae276 -
IET Nanobiotechnology 2024Diabetic nephropathy (DN) is the leading cause of chronic kidney disease, and the activation and infiltration of phagocytes are critical steps of DN. This study aimed to...
BACKGROUND
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease, and the activation and infiltration of phagocytes are critical steps of DN. This study aimed to explore the mechanism of exosomes in macrophages and diabetes nephropathy and the role of miRNA-34a, which might provide a new path for treating DN.
MATERIALS AND METHODS
The DN model was established, and the success of the model establishment was confirmed by detecting general indicators, HE staining, and immunohistochemistry. Electron microscopy and NanoSight Tracking Analysis (NTA) were used to see the morphology and size of exosomes. MiRNA-34a inhibitor, miRNA-34a mimics, pc-, and controls were transfected in macrophages with or without kidney exosomal. A dual-luciferase reporter gene experiment verifies the targeting relationship between miRNA-34a and . After exosomal culture, macrophages are co-cultured with normal renal tubular cells to detect renal tubular cell fibrosis. Q-PCR and western blot were undertaken to detect related RNA and proteins.
RESULTS
An animal model of diabetic nephropathy was successfully constructed. Macrophages could phagocytose exosomes. After ingesting model exosomes, M1 macrophages were activated, while M2 macrophages were weakened, indicating the model mice's kidney exosomes caused the polarization. MiRNA-34a inhibitor increased expression. MiRNA-34a expressed higher in diabetic nephropathy Model-Exo. MiRNA-34a negatively regulated . rescued macrophage polarization and renal tubular cell fibrosis.
CONCLUSION
Exosomal miRNA-34a of tubular epithelial cells promoted M1 macrophage activation in diabetic nephropathy via negatively regulating expression, which may provide a new direction for further exploration of DN treatment.
Topics: MicroRNAs; Diabetic Nephropathies; Animals; Exosomes; Mice; Macrophages; Fibrosis; Male; Kidney Tubules; Mice, Inbred C57BL; Disease Models, Animal; Diabetes Mellitus, Experimental
PubMed: 38863972
DOI: 10.1049/2024/5702517 -
Frontiers in Endocrinology 2024Serum lipids were found to be correlated with chronic kidney disease and cardiovascular disease. Here, we aimed to research the potential causal associations between...
BACKGROUND
Serum lipids were found to be correlated with chronic kidney disease and cardiovascular disease. Here, we aimed to research the potential causal associations between five serum lipid parameters and the risk of diabetic nephropathy using several Mendelian Randomization methods.
METHODS
Genetic data was obtained from the UK Biobank datasets. Causal effects were estimated using multiple MR methods. Heterogeneity and pleiotropy tests were performed.
RESULTS
MR analysis revealed that HDL-C and TG exhibited causal associations with diabetic nephropathy (<0.05). Similar trends were not observed for other lipid parameters.
CONCLUSIONS
Our research has suggested links between HDL-C, TG and diabetic nephropathy. The findings could contribute to further elucidation of the disease etiology.
STRENGTHS AND LIMITATIONS OF THIS STUDY
This article only uses Mendel randomization method to analyze the relationship between blood lipids and diabetes nephropathy, which is more convincing when combined with population data.
Topics: Humans; Mendelian Randomization Analysis; Diabetic Nephropathies; Lipids; Cholesterol, HDL; Triglycerides; Male; Female; Polymorphism, Single Nucleotide; Risk Factors; Middle Aged
PubMed: 38863932
DOI: 10.3389/fendo.2024.1358358 -
Frontiers in Endocrinology 2024The aim of this cross-sectional study was to elucidate the associations between various domains of physical activity, such as occupation-related (OPA),...
BACKGROUND
The aim of this cross-sectional study was to elucidate the associations between various domains of physical activity, such as occupation-related (OPA), transportation-related (TPA), leisure-time (LTPA) and overall physical activity (PA), and diabetic kidney disease.
METHODS
Our study encompassed 2,633 participants, drawn from the cross-sectional surveys of the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018, and employed survey-weighted logistic regression, generalized linear regression, and restricted cubic spline (RCS) analyses to ascertain the relationship between different domains of physical activity and diabetic kidney disease.
RESULTS
After controlling for all confounders, multivariate logistic regression analyses revealed a lack of correlation between the various domains of physical activity and the prevalence of diabetic kidney disease. Multiple generalized linear regression analyses showed that durations of PA (β = 0.05, 95% CI, 0.01-0.09, P = 0.012) and TPA (β = 0.32, 95% CI, 0.10-0.55, P = 0.006) were positively associated with eGFR levels; and LTPA durations were inversely associated with UACR levels (β = -5.97, 95% CI, -10.50 - -1.44, P = 0.011). The RCS curves demonstrated a nonlinear relationship between PA, OPA, and eGFR, as well as a nonlinear correlation between PA and ACR. Subgroup and sensitivity analyses largely aligned with the outcomes of the multivariate generalized linear regression, underscoring the robustness of our findings.
CONCLUSION
Our population-based study explored the association between different domains of physical activity and diabetic kidney disease. Contrary to our expectations, we found no significant association between the duration of physical activity across all domains and the prevalence of diabetic nephropathy. Nonetheless, renal function markers, including eGFR and UACR, exhibited significant correlations with the duration of total physical activity (TPA) and leisure-time physical activity (LTPA), respectively, among diabetic patients. Interestingly, our findings suggest that diabetic patients engage in physical activity to preserve renal function, ensuring moderate exercise durations not exceeding 35 hours per week.
Topics: Humans; Male; Female; Exercise; Cross-Sectional Studies; Middle Aged; Diabetic Nephropathies; Nutrition Surveys; Adult; Leisure Activities; Aged; Glomerular Filtration Rate; Prevalence
PubMed: 38863925
DOI: 10.3389/fendo.2024.1364028 -
BMC Genomics Jun 2024Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver....
BACKGROUND
Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes.
METHODS
We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients.
RESULTS
Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR.
CONCLUSIONS
We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.
Topics: Humans; Male; Mitochondria; Female; Middle Aged; Genetic Predisposition to Disease; Glomerular Filtration Rate; Genetic Variation; Haplotypes; Renal Insufficiency, Chronic; DNA, Mitochondrial; Diabetes Mellitus, Type 1; Polymorphism, Single Nucleotide; Adult; Aged
PubMed: 38858654
DOI: 10.1186/s12864-024-10449-1 -
Nutrition & Diabetes Jun 2024Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose...
BACKGROUND
Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose tissue (PRAT) or the intestinal flora and its metabolites (trimethylamine N-oxide, TMAO) is unclear.
METHODS
DKD mice were received different concentrations of 1,25-(OH)D for 2 weeks. Serum TNF-α levels and TMAO levels were detected. 16S rRNA sequencing was used to analyze gut microbiota. qPCR was used to detect the expression of TLR4, NF-Κb, PGC1α, and UCP-1 in kidney and adipose tissue. Histological changes in kidney and perirenal adipose tissue were observed using HE, PAS, Masson and oil red staining. Immunofluorescence and immunohistochemistry were used to detect the expression of VDR, PGC1α, podocin, and UCP-1 in kidney and adipose tissue. Electron microscopy was used to observe the pathological changes in the kidney. VDR knockout mice were constructed to observe the changes in the gut and adipose tissue, and immunofluorescence and immunohistochemistry were used to detect the expression of UCP-1 and collagen IV in the kidney.
RESULTS
1,25-(OH)D could improve the dysbiosis of the intestinal flora of mice with DKD, increase the abundance of beneficial bacteria, decrease the abundance of harmful bacteria, reduce the pathological changes in the kidney, reduce fat infiltration, and downregulate the expression of TLR4 and NF-κB in kidneys. The serum TMAO concentration in mice with DKD was significantly higher than that of the control group, and was significantly positively correlated with the urine ACR. In addition, vitamin D stimulated the expression of the surface markers PGC1α, UCP-1 and VDR in the PRAT in DKD mice, and TMAO downregulated the expression of PRAT and renal VDR.
CONCLUSIONS
The protective effect of 1,25-(OH)D in DKD mice may affect the intestinal flora and its related metabolite TMAO on perirenal fat and kidneys.
Topics: Animals; Gastrointestinal Microbiome; Mice; Kidney; Methylamines; Male; Receptors, Calcitriol; Mice, Knockout; Diabetic Nephropathies; Adipose Tissue; Mice, Inbred C57BL; Vitamin D; Calcitriol
PubMed: 38858392
DOI: 10.1038/s41387-024-00297-z -
La Revue de Medecine Interne Jun 2024
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Kidney; Cardiovascular Diseases; Hypoglycemic Agents; Heart; Diabetic Nephropathies
PubMed: 38857975
DOI: 10.1016/j.revmed.2024.05.026 -
JCI Insight Jun 2024Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was...
Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.
Topics: Humans; Diabetic Nephropathies; Animals; Mice; Lactic Acid; Female; Male; Glycolysis; Middle Aged; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Mitochondria; Adult; Glomerular Filtration Rate; Aged; Kidney Tubules, Proximal; Glucose; Oxidative Phosphorylation; Biomarkers; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 38855868
DOI: 10.1172/jci.insight.168825 -
ACS Omega Jun 2024has been the subject of plentiful studies due to its purported health advantages; nevertheless, additional investigation is required to determine whether several...
has been the subject of plentiful studies due to its purported health advantages; nevertheless, additional investigation is required to determine whether several chronic diseases may be treated or avoided with its nanoform. Therefore, we set out to examine nanoparticles (SNPs) to protect against kidney impairment caused by Streptozotocin (STZ) in diabetic rats, precisely focusing on its effect and the cellular intracellular pathways involved. Male Wistar rats were assigned into four groups: Group 1 was set as control, comprising the normal rats; group 2 was administered SNPs (0.5 mg/kg BW, once/day) orally for 84 consecutive days; group 3, STZ-diabetic rats were injected with STZ (65 mg/kg BW); and group 4, in which the diabetic rats were treated with SNPs. After inducing diabetes in rats for 84 days, the animals were euthanized. The results disclosed that SNP treatment substantially ( < 0.05) improved the glucose and glycated hemoglobin levels (HbA1c %), insulin, C-peptide, and cystatin C deterioration in diabetic rats. Furthermore, SNP administration significantly lowered ( < 0.05) nitric oxide (NO) and malondialdehyde (MDA) levels in renal tissue and enhanced kidney function metrics, as well as improved the antioxidant capacity of the renal tissue. In addition, oral SNPs overcame the diabetic complications concerning diabetic nephropathy, indicated by downregulation and upregulation of apoptotic and antiapoptotic genes, respectively, along with prominent modulation of the antiangiogenic marker countenance level, improving kidney function. SNP modulated the nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 (NRF2/HO-1) pathways and inhibited the nuclear factor-κB (NF-κB) expression, strengthening the SNP pathways in alleviating diabetic nephropathy. The histopathology results corroborated the obtained biochemical and molecular observations, suggesting the therapeutic potential of SNPs in diabetic nephropathy via mechanisms other than its significant antioxidant and hypoglycemic effects, including modulation of antiangiogenic and inflammatory mediators and the NRF2/HO-1 pathways.
PubMed: 38854532
DOI: 10.1021/acsomega.4c02285