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Microbiology Spectrum Aug 2022Diabetic nephropathy (DN) is the primary cause of end-stage renal disease. Accumulating studies have implied a critical role for the gut microbiota in diabetes mellitus...
Diabetic nephropathy (DN) is the primary cause of end-stage renal disease. Accumulating studies have implied a critical role for the gut microbiota in diabetes mellitus (DM) and DN. However, the precise roles and regulatory mechanisms of the gut microbiota in the pathogenesis of DN remain largely unclear. In this study, metagenomics sequencing was performed using fecal samples from healthy controls (CON) and type 2 diabetes mellitus (T2DM) patients with or without DN. Fresh fecal samples from 15 T2DM patients without DN, 15 DN patients, and 15 age-, gender-, and body mass index (BMI)-matched healthy controls were collected. The compositions and potential functions of the gut microbiota were estimated. Although no difference of gut microbiota α and β diversity was observed between the CON, T2DM, and DN groups, the relative abundances of butyrate-producing bacteria (, , and Roseburia intestinalis) and potential probiotics ( and ) were significantly reduced in T2DM and DN patients. Besides, Bacteroides stercoris was significantly enriched in fecal samples from patients with DN. Moreover, sp. 26_22 was negatively associated with serum creatinine ( < 0.05). DN patients could be accurately distinguished from CON by sp. CAG_768 (area under the curve [AUC] = 0.941), Bacteroides propionicifaciens (AUC = 0.905), and sp. CAG_715 (AUC = 0.908). DN patients could be accurately distinguished from T2DM patients by , Fusobacterium varium, and sp. MSX73 (AUC = 0.889). Regarding the potential bacterial functions of the gut microbiota, the citrate cycle, base excision repair, histidine metabolism, lipoic acid metabolism, and bile acid biosynthesis were enriched in DN patients, while selenium metabolism and branched-chain amino acid biosynthesis were decreased in DN patients. Gut microbiota imbalance is found in fecal samples from DN patients, in which Roseburia intestinalis is significantly decreased, while Bacteroides stercoris is increased. There is a significant correlation between gut microbiota imbalance and clinical indexes related to lipid metabolism, glucose metabolism, and renal function. The gut microbiota may be predictive factors for the development and progression of DN, although further studies are warranted to illustrate their regulatory mechanisms.
Topics: Bacteroides; Clostridiales; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gastrointestinal Microbiome; Humans
PubMed: 35863004
DOI: 10.1128/spectrum.00324-22 -
Frontiers in Endocrinology 2022Cystatin C, an inhibitor of cysteine protease, has been used as a biomarker for estimating glomerular filtration rate. However, the causal relation between cystatin C...
AIMS
Cystatin C, an inhibitor of cysteine protease, has been used as a biomarker for estimating glomerular filtration rate. However, the causal relation between cystatin C and diabetic nephropathy remains uncertain.
METHODS
We assessed the causal effect of cystatin C together with other five serum biomarkers including KIM-1, GDF-15, TBIL, uric acid, and Scr on diabetic nephropathy by Mendelian randomization (MR) analysis. 234 genetic variants were selected as instrumental variables to evaluate the causal effect of cystatin C (N=361194) on diabetic nephropathy (Ncase/Ncontrol up to 3283/210463). Multivariable MR (MVMR) was performed to assess the stability of cystatin C's causal relationship. Two-step MR was used to assess the mediation effect of BMI and SBP.
RESULTS
Among the six serum biomarkers, only cystatin C causally associated with diabetic nephropathy (IVW OR: 1.36, 95%CI [1.15, 1.61]). After adjusting for the potential confounders BMI and SBP, cystatin C maintained its causal effect on the DN (OR: 1.17, 95%CI [1.02, 1.33]), which means that the risk of DN increased by 17% with an approximate 1 standard deviation (SD) increment of serum cystatin C level. Two-step MR results indicated that BMI might mediate the causal effect of cystatin C on diabetic nephropathy.
INTERPRETATION
Our findings discovered that cystatin C was a risk factor for diabetic nephropathy independent of BMI and SBP in diabetes mellitus patients. Future research is required to illustrate the underlying mechanism and prove targeting circulating cystatin C could be a potential therapy method.
Topics: Humans; Cystatin C; Diabetes Mellitus; Diabetic Nephropathies; Mendelian Randomization Analysis
PubMed: 36482996
DOI: 10.3389/fendo.2022.1043174 -
Frontiers in Endocrinology 2023Diabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian...
BACKGROUND
Diabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian randomization (MR) is a genetic tool that is widely used to minimize confounding and reverse causation when identifying the causal effects of complex traits. In this study, we conducted an integrated multiple microarray analysis and large-scale plasma proteome MR analysis to identify candidate biomarkers and evaluate the causal effects of prospective therapeutic targets in DN.
METHODS
Five DN gene expression datasets were selected from the Gene Expression Omnibus. The robust rank aggregation (RRA) method was used to integrate differentially expressed genes (DEGs) of glomerular samples between patients with DN and controls, followed by functional enrichment analysis. Protein quantitative trait loci were incorporated from seven different proteomic genome-wide association studies, and genetic association data on DN were obtained from FinnGen (3676 cases and 283,456 controls) for two-sample MR analysis. External validation and clinical correlation were also conducted.
RESULTS
A total of 82 DEGs (53 upregulated and 29 downregulated) were identified through RRA integrated analysis. The enriched Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways of the DEGs were significantly enriched in neutrophil degranulation, neutrophil activation, proteoglycan binding, collagen binding, secretory granule lumen, gluconeogenesis, tricarboxylic acid cycle, and pentose phosphate pathways. MR analysis revealed that the genetically predicted levels of MHC class I polypeptide-related sequence B (MICB), granzyme A (GZMA), cathepsin S (CTSS), chloride intracellular channel protein 5, and ficolin-1 (FCN1) were causally associated with DN risk. Expression validation and clinical correlation analysis showed that MICB, GZMA, FCN1, and insulin-like growth factor 1 may participate in the development of DN, and carbonic anhydrase 2 and lipoprotein lipase may play protective roles in patients with DN.
CONCLUSION
Our integrated analysis identified novel biomarkers, including MICB and GZMA, which may help further understand the complicated mechanisms of DN and identify new target pathways for intervention.
Topics: Humans; Diabetic Nephropathies; Gene Expression Profiling; Genome-Wide Association Study; Proteomics; Mendelian Randomization Analysis; Microarray Analysis; Biomarkers; Quantitative Trait Loci; Diabetes Mellitus
PubMed: 37492198
DOI: 10.3389/fendo.2023.1191768 -
Renal Failure Dec 2023Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte...
Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN. DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2. TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells. Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis Nrf2/ROS/NLRP3 axis.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Nephropathies; Heme Oxygenase-1; Inflammasomes; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Podocytes; Reactive Oxygen Species
PubMed: 36938748
DOI: 10.1080/0886022X.2023.2165103 -
The American Journal of Chinese Medicine 2023Diabetic nephropathy (DN) is thought to be the major cause of end-stage renal disease. Due to its complicated pathogenesis and the low efficacy of DN treatment, a deep...
Diabetic nephropathy (DN) is thought to be the major cause of end-stage renal disease. Due to its complicated pathogenesis and the low efficacy of DN treatment, a deep understanding of new etiological factors may be useful. Ferroptosis, a nonapoptotic form of cell death, is characterized by the accumulation of iron-dependent lipid peroxides to lethal levels. Ferroptosis-triggered renal tubular injury is reported to participate in the development of DN, and blocking ferroptosis might be an effective strategy to prevent the development of DN. Quercetin (QCT), a natural flavonoid that is present in a variety of fruits and vegetables, has been reported to ameliorate DN. However, its underlying nephroprotective mechanism is unclear. Herein, we explored the antiferroptosic effect of QCT and verified its nephroprotective effect using DN mice and high glucose (HG)-incubated renal tubular epithelial cell models. We found HG-induced abnormal activation of ferroptosis of renal tubular epithelial cells, and QCT treatment inhibited ferroptosis by downregulating the expression of transferrin receptor 1 (TFR-1) and upregulating the expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH-1), and the cystine/glutamate reverse antiporter solute carrier family 7 member (SLC7A11) in DN mice and HG-incubated HK-2 cells. Subsequently, both and results confirmed that QCT activated the NFE2-related factor 2 (Nrf2)/Heme oxygenase-1(HO-1) signaling pathway by increasing the levels of Nrf2 and HO-1. Therefore, this study supports that QCT inhibits the ferroptosis of renal tubular epithelial cells by regulating the Nrf2/HO-1 signaling pathway, providing a novel insight into the protective mechanism of QCT in DN treatment.
Topics: Animals; Mice; Diabetic Nephropathies; Quercetin; NF-E2-Related Factor 2; Ferroptosis; Signal Transduction; Diabetes Mellitus
PubMed: 37046368
DOI: 10.1142/S0192415X23500465 -
Journal of Nephrology Oct 2020Chronic kidney disease is associated with altered lipid metabolism and lipid accumulation. Although it is though that hyperlipemia is a consequence of kidney... (Review)
Review
Chronic kidney disease is associated with altered lipid metabolism and lipid accumulation. Although it is though that hyperlipemia is a consequence of kidney dysfunction, several lines of evidence support that hyperlipidemia may contribute to the onset and progression of kidney disease, also in diabetes. This review describes the results of recent observational studies supporting the concept that glucose is only partly responsible for kidney damage onset, while a cluster of factors, including hypertriglyceridemia and low HDL-cholesterol, could play a relevant role in inducing onset and progression of DKD. We also report the results of randomized clinical trials investigating in type 2 diabetic patients the role of drug improvement of hypertriglyceridemia on renal outcomes. Finally, we discuss putative mechanisms linking hyperlipidemia (i.e. hypertriglyceridemia or low HDL cholesterol) with kidney disease.
Topics: Atherosclerosis; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dyslipidemias; Humans; Kidney; Triglycerides
PubMed: 32328901
DOI: 10.1007/s40620-020-00739-8 -
Food & Function May 2023Few epidemiological studies have investigated the relationship between flavonoids and diabetic nephropathy (DN). Therefore, we explored the association between dietary...
Few epidemiological studies have investigated the relationship between flavonoids and diabetic nephropathy (DN). Therefore, we explored the association between dietary flavonoid intake and DN among 1949 US adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2008, 2009-2010, and 2017-2018. Weighted logistic regression models demonstrated that the total flavonoid intake in the second (OR: 0.642; 95% CI: 0.456-0.906), third (OR: 0.665; 95% CI: 0.447-0.988), and the highest (OR: 0.551; 95% CI: 0.382-0.796) quantiles ( the lowest) were associated with the decreased risk of DN. Restricted cubic spline (RCS) analyses showed that the total flavonoid intake had a negative linear association with DN (-value for non-linearity was 0.003). Weighted quantile sum (WQS) regression analyses revealed that flavan-3-ols, flavones, and anthocyanidins were the main contributors for the combined effects of six flavonoid subclasses. Our findings suggested that higher dietary flavonoid intake was associated with a decreased risk of DN, with the greatest influence coming from flavan-3-ols, flavones, and anthocyanidins.
Topics: Adult; Humans; Flavonoids; Nutrition Surveys; Anthocyanins; Diet; Diabetic Nephropathies; Polyphenols; Flavones; Logistic Models; Risk Factors; Diabetes Mellitus
PubMed: 37066968
DOI: 10.1039/d3fo00242j -
Stem Cell Research & Therapy Apr 2022Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and a common cause of end-stage renal disease (ESRD). Mesenchymal stem cells (MSCs) possess...
MicroRNA-146a-5p-modified human umbilical cord mesenchymal stem cells enhance protection against diabetic nephropathy in rats through facilitating M2 macrophage polarization.
BACKGROUND
Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and a common cause of end-stage renal disease (ESRD). Mesenchymal stem cells (MSCs) possess potent anti-inflammatory and immunomodulatory properties, which render them an attractive therapeutic tool for tissue damage and inflammation.
METHODS
This study was designed to determine the protective effects and underlying mechanisms of human umbilical cord-derived MSCs (UC-MSCs) on streptozotocin-induced DN. Renal function and histological staining were used to evaluate kidney damage. RNA high-throughput sequencing on rat kidney and UCMSC-derived exosomes was used to identify the critical miRNAs. Co-cultivation of macrophage cell lines and UC-MSCs-derived conditional medium were used to assess the involvement of macrophage polarization signaling.
RESULTS
UC-MSC administration significantly improved renal function, reduced the local and systemic inflammatory cytokine levels, and attenuated inflammatory cell infiltration into the kidney tissue in DN rats. Moreover, UC-MSCs shifted macrophage polarization from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. Mechanistically, miR-146a-5p was significantly downregulated and negatively correlated with renal injury in DN rats as determined through high-throughput RNA sequencing. Importantly, UC-MSCs-derived miR-146a-5p promoted M2 macrophage polarization by inhibiting tumor necrosis factor receptor-associated factor-6 (TRAF6)/signal transducer and activator of transcription (STAT1) signaling pathway. Furthermore, miR-146a-5p modification in UC-MSCs enhanced the efficacy of anti-inflammation and renal function improvement.
CONCLUSIONS
Collectively, our findings demonstrate that UC-MSCs-derived miR-146a-5p have the potential to restore renal function in DN rats through facilitating M2 macrophage polarization by targeting TRAF6. This would pave the way for the use of miRNA-modified cell therapy for kidney diseases.
Topics: Animals; Anti-Inflammatory Agents; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Macrophages; Male; Mesenchymal Stem Cells; MicroRNAs; Rats; TNF Receptor-Associated Factor 6; Umbilical Cord
PubMed: 35477552
DOI: 10.1186/s13287-022-02855-7 -
Clinics in Geriatric Medicine Aug 2020Diabetes and diabetic nephropathy have become more prevalent in the elderly population. Diabetic nephropathy has become increasingly prevalent in the elderly population.... (Review)
Review
Diabetes and diabetic nephropathy have become more prevalent in the elderly population. Diabetic nephropathy has become increasingly prevalent in the elderly population. The presence of this disease in an age group suffering multiple comorbidities has altered the pathophysiology and leading cause of mortality. Mortality has become linked more often to cardiovascular events rather than progression of end-stage-renal-disease, which explains the recent shift of focus of trials to improving cardiovascular-outcomes in patients with diabetes. In this chapter, we emphasize the difference in treatment modalities and goals of therapy in elderly versus young. In addition, we discuss results from recent outcome trials with regards to renal benefits of sodium-glucose co-transporter-2-inhibitors and glucagon-like peptide-1-receptor-agonists.
Topics: Aged; Albuminuria; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Humans; Hypoglycemic Agents; Kidney; Renal Insufficiency, Chronic
PubMed: 32586473
DOI: 10.1016/j.cger.2020.04.004 -
Clinical and Experimental Nephrology Jul 2020Proteinuria has been considered to be the hallmark of diabetic kidney disease and to precede renal function loss. However, it has become clear that a substantial... (Review)
Review
Proteinuria has been considered to be the hallmark of diabetic kidney disease and to precede renal function loss. However, it has become clear that a substantial proportion of patients either with type 1 diabetes or type 2 diabetes have renal function loss without proteinuria, known as nonproteinuric diabetic kidney disease. Despite increasing recognition of the prevalence of nonproteinuric diabetic kidney disease, data on this phenotype of diabetic kidney disease is sparse. This review describes ever known clinical and pathological manifestations, renal prognosis, and mortality in patient with nonproteinuric diabetic kidney disease.
Topics: Blood Pressure; Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Lipids; Phenotype; Prognosis; Progression-Free Survival; Proteinuria
PubMed: 32236782
DOI: 10.1007/s10157-020-01881-0