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International Journal of Molecular... Jun 2024Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as...
Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as three isoforms, namely, NMNAT1, NMNAT2, and NMNAT3, encoded by , , and , respectively. In diabetic nephropathy (DN), NAD levels decrease, aggravating renal fibrosis. Conversely, sodium-glucose cotransporter-2 inhibitors increase NAD levels, mitigating renal fibrosis. In this regard, renal NAD synthesis has recently gained attention. However, the renal role of in DN remains uncertain. Therefore, we investigated the role of by establishing genetically engineered mice. Among the three isoforms, NMNAT1 levels were markedly reduced in the proximal tubules (PTs) of db/db mice. We examined the phenotypic changes in PT-specific conditional knockout (CKO) mice. In CKO mice, expression in PTs was downregulated when the tubules exhibited albuminuria, peritubular type IV collagen deposition, and mitochondrial ribosome (mitoribosome) excess. In CKO mice, deficiency-induced mitoribosome excess hindered mitoribosomal translation of mitochondrial inner membrane-associated oxidative phosphorylation complex I (CI), CIII, CIV, and CV proteins and mitoribosomal dysfunction. Furthermore, the expression of hypermethylated in cancer 1, a transcription repressor, was downregulated in CKO mice, causing mitoribosome excess. overexpression preserved mitoribosomal function, suggesting its protective role in DN.
Topics: Animals; Diabetic Nephropathies; Mice; Nicotinamide-Nucleotide Adenylyltransferase; Mice, Knockout; Kidney Tubules, Proximal; Male; Mitochondria; Mice, Inbred C57BL
PubMed: 38928090
DOI: 10.3390/ijms25126384 -
Biomedicines May 2024Glomerular diseases (GDs), significant causes of end-stage kidney disease, are better understood through epidemiological studies based on kidney biopsies (KBs), which...
Glomerular diseases (GDs), significant causes of end-stage kidney disease, are better understood through epidemiological studies based on kidney biopsies (KBs), which provide important insights into their prevalence and characteristics. This study aims to analyze the clinicopathological features of GDs diagnosed from 2008 to 2017 at Romania's largest reference center. In this decade-long study, 1254 adult patients diagnosed with GDs were included. The local previously validated renal histopathological prognostic score was calculated for each KB using four histopathologic lesions: global glomerulosclerosis, tubular atrophy, interstitial fibrosis and fibrocellular/fibrous crescents. The mean patient age was 50 years, with a male predominance (57%). The primary referral reasons were nephrotic syndrome (46%), nephritic syndrome (37%), chronic kidney disease (12%), asymptomatic urinary abnormalities (4%), and acute kidney injury (1%). Immunoglobulin A nephropathy (IgAN) was the most frequently diagnosed GD (20%), aligning with frequencies reported in European registries. Diabetic glomerular nephropathy was the most common secondary GD (10%). It also presented the highest median renal histopathological prognostic score (2), indicating a poorer prognosis. Lower eGFR and higher proteinuria were independently associated with higher scores. This decade-long study highlights IgAN as the most frequent GD diagnosed by KB. Diabetic glomerular nephropathy was identified as the most common secondary GD. The renal histopathological prognostic score, notably high in diabetic glomerular nephropathy patients, was correlated with lower eGFR and higher proteinuria, underlining its clinical relevance.
PubMed: 38927350
DOI: 10.3390/biomedicines12061143 -
Biomolecules Jun 2024Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and the main cause of end-stage renal disease around the world. Mitochondria are the... (Review)
Review
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and the main cause of end-stage renal disease around the world. Mitochondria are the main organelles responsible for producing energy in cells and are closely involved in maintaining normal organ function. Studies have found that a high-sugar environment can damage glomeruli and tubules and trigger mitochondrial dysfunction. Meanwhile, animal experiments have shown that DKD symptoms are alleviated when mitochondrial damage is targeted, suggesting that mitochondrial dysfunction is inextricably linked to the development of DKD. This article describes the mechanisms of mitochondrial dysfunction and the progression and onset of DKD. The relationship between DKD and mitochondrial dysfunction is discussed. At the same time, the progress of DKD treatment targeting mitochondrial dysfunction is summarized. We hope to provide new insights into the progress and treatment of DKD.
Topics: Diabetic Nephropathies; Humans; Mitochondria; Animals
PubMed: 38927136
DOI: 10.3390/biom14060733 -
The Tohoku Journal of Experimental... Jun 2024
PubMed: 38925954
DOI: 10.1620/tjem.2024.J048 -
The Journal of Biological Chemistry Jun 2024Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin...
Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin analogues can delay the progression of DN, but the mechanism is not fully understood. In this study, we found that low molecular weight heparin (LMWH) therapy significantly upregulated some downstream proteins of the peroxisome proliferator-activated receptor (PPAR) signaling pathway by label-free quantification of the mouse kidney proteome. Through cell model verification, LMWH can protect the heparan sulfate (HS) of renal tubular epithelial cells from being degraded by heparanase that is highly expressed in a high-glucose environment, enhance the endocytic recruitment of fatty acid-binding protein 1 (FABP1), a coactivator of the PPAR pathway, and then regulate the activation level of intracellular PPAR. In addition, we have elucidated for the first time the molecular mechanism of HS and FABP1 interaction. These findings provide new insights into understanding the role of heparin in the pathogenesis of DN and developing corresponding treatments.
PubMed: 38925330
DOI: 10.1016/j.jbc.2024.107493 -
Journal of Diabetes Jul 2024Previous studies have shown that the red cell distribution width (RDW)/serum albumin ratio (RA) is an integrative and new inflammatory marker. RA is associated with...
BACKGROUND
Previous studies have shown that the red cell distribution width (RDW)/serum albumin ratio (RA) is an integrative and new inflammatory marker. RA is associated with clinical outcomes in a variety of diseases, but the clinical value of RDW/RA in the assessment of diabetic kidney disease (DKD) has not been elucidated. We examined the link between diabetic RA and DKD while controlling for a wide variety of possible confounders.
METHODS
Retrospective cohort analysis of the National Health and Nutrition Examination Survey (NHANES: 2009-2018) database from the Second Affiliated Hospital and Yuying Children's Hospital and the Wenzhou Medical University (WMU) database was conducted. Multivariate logistic regression analysis was used to assess the association between RA and DKD.
RESULTS
Overall, 4513 diabetic patients from the NHANES database (n = 2839) and the WMU (n = 1412) were included in this study; 974 patients were diagnosed with DKD in NHANES and 462 in WMU. In the NHANES cohort, diabetes mellitus (DM) patients with higher RA level had a higher risk of DKD (odds ratio = 1.461, 95% confidence interval: 1.250-1.707, p < 0.00001). After adjusting for confounders and propensity score-matched (PSM) analysis, both shown RA levels were independently linked to DKD (p = 0.00994, p = 0.02889). Similar results were also observed in the WMU cohort (p < 0.00001).
CONCLUSIONS
The study observes that the RA was an independent predictor of DKD in DM patients. The RA, a biomarker that is cost-effective and easy-to-access, may have potential for risk stratification of DKD.
Topics: Humans; Male; Female; Retrospective Studies; Middle Aged; Diabetic Nephropathies; Erythrocyte Indices; Biomarkers; Serum Albumin; Nutrition Surveys; Adult; Aged; Risk Factors
PubMed: 38923843
DOI: 10.1111/1753-0407.13575 -
Hong Kong Medical Journal = Xianggang... Jun 2024
PubMed: 38918067
DOI: 10.12809/hkmj245162 -
Pharmacological Research Jun 2024The longevity protein sirtuins (SIRTs) belong to a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. In mammals, SIRTs comprise seven members... (Review)
Review
The longevity protein sirtuins (SIRTs) belong to a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. In mammals, SIRTs comprise seven members (SIRT1-7) which are localized to different subcellular compartments. As the most prominent mitochondrial deacetylases, SIRT3 is known to be regulated by various mechanisms and participate in virtually all aspects of mitochondrial homeostasis and metabolism, exerting significant impact on multiple organs. Notably, the kidneys possess an abundance of mitochondria that provide substantial energy for filtration and reabsorption. A growing body of evidence now supports the involvement of SIRT3 in several renal diseases, including acute kidney injury, chronic kidney disease, and diabetic nephropathy; notably, these diseases are all associated with aging. In this review, we summarize the emerging role of SIRT3 in renal diseases and aging, and highlights the intricate mechanisms by which SIRT3 exerts its effects. In addition, we highlight the potential therapeutic significance of modulating SIRT3 and provide valuable insights into the therapeutic role of SIRT3 in renal diseases to facilitate clinical application.
PubMed: 38917912
DOI: 10.1016/j.phrs.2024.107261 -
Frontiers in Endocrinology 2024The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or...
OBJECTIVE
The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients.
METHODS
We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model.
RESULTS
For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1μmol/L, Cit higher than 26 μmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR.
CONCLUSION
Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.
Topics: Humans; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Machine Learning; Male; Female; Middle Aged; Aged; Biomarkers; Metabolomics; Carnitine; Cohort Studies; Diabetic Nephropathies
PubMed: 38915893
DOI: 10.3389/fendo.2024.1279034 -
JCI Insight Jun 2024Our previous study identified 8 risk and 9 protective plasma miRNAs associated with progression to end-stage kidney disease (ESKD) in diabetes. This study aimed to...
Our previous study identified 8 risk and 9 protective plasma miRNAs associated with progression to end-stage kidney disease (ESKD) in diabetes. This study aimed to elucidate preanalytical factors that influence the quantification of circulating miRNAs. Using the EdgeSeq platform, which quantifies 2,002 miRNAs in plasma, including ESKD-associated miRNAs, we compared miRNA profiles in whole plasma versus miRNA profiles in RNA extracted from the same plasma specimens. Less than half of the miRNAs were detected in standard RNA extraction from plasma. Detection of individual and concentrations of miRNAs were much lower when RNA extracted from plasma was quantified by RNA sequencing (RNA-Seq) or quantitative reverse transcription PCR (qRT-PCR) platforms compared with EdgeSeq. Plasma profiles of miRNAs determined by the EdgeSeq platform had excellent reproducibility in assessment and had no variation with age, sex, hemoglobin A1c, BMI, and cryostorage time. The risk ESKD-associated miRNAs were detected and measured accurately only in whole plasma and using the EdgeSeq platform. Protective ESKD-associated miRNAs were detected by all platforms except qRT-PCR; however, correlations among concentrations obtained with different platforms were weak or nonexistent. In conclusion, preanalytical factors have a profound effect on detection and quantification of circulating miRNAs in ESKD in diabetes. Quantification of miRNAs in whole plasma and using the EdgeSeq platform may be the preferable method to study profiles of circulating cell-free miRNAs associated with ESKD and possibly other diseases.
Topics: Humans; Circulating MicroRNA; Kidney Failure, Chronic; Male; Female; Middle Aged; Diabetic Nephropathies; Biomarkers; Aged; Reproducibility of Results; Adult; MicroRNAs; Disease Progression; Diabetes Mellitus
PubMed: 38912578
DOI: 10.1172/jci.insight.174153