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Drug Design, Development and Therapy 2021Oxidative stress and inflammation play essential roles in the development and progression of diabetic nephropathy (DN). Baicalin (BAI), a natural flavonoid, has been...
BACKGROUND
Oxidative stress and inflammation play essential roles in the development and progression of diabetic nephropathy (DN). Baicalin (BAI), a natural flavonoid, has been showed to have a renoprotective effect in various renal diseases. However, its underlying mechanisms in DN remain unclear. In this study, we explored the potential effects and underlying mechanisms of BAI on DN using a spontaneous DN model.
METHODS
The protective effects of BAI on DN have been evaluated by detecting DN-related biochemical indicators, kidney histopathology and cell apoptosis. After that, we examined the level of renal oxidative stress and inflammation to explain BAI's renoprotective effects. Then, Nrf2 pathway was tested to clarify its antioxidant activity, and kidney transcriptomics was conducted to elucidate its anti-inflammatory activity. Finally, Western blot was applied for final mechanism verification.
RESULTS
Our results found that BAI effectively ameliorated diabetic conditions, proteinuria, renal histopathological changes and cell apoptosis in DN. BAI significantly improved the kidney levels of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and catalase (CAT), and reduced malondialdehyde (MDA) level. Meanwhile, the infiltration of inflammatory cells including T-lymphocytes, T-helper cells, neutrophils and macrophages, and the mRNA levels of pro-inflammatory cytokines (IL-1β, IL-6, MCP-1 and TNFα) were also obviously inhibited by BAI. Afterward, Western blot found that BAI significantly activated Nrf2 signaling and increased the expression of downstream antioxidant enzymes (HO-1, NQO-1). Kidney transcriptomics revealed that the inhibition of MAPK signaling pathway may contribute to BAI's anti-inflammatory activity, which has also been verified in later experiment. BAI treatment did obviously inhibit the activation of canonical pro-inflammatory signaling pathway MAPK family, such as Erk1/2, JNK and P38.
CONCLUSION
In summary, our data demonstrated that BAI can treat DN by alleviating oxidative stress and inflammation, and its underlying mechanisms were associated with the activation of Nrf2-mediated antioxidant signaling pathway and the inhibition of MAPK-mediated inflammatory signaling pathway.
Topics: Animals; Apoptosis; Diabetic Nephropathies; Flavonoids; Inflammation; MAP Kinase Signaling System; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress
PubMed: 34321869
DOI: 10.2147/DDDT.S319260 -
Journal of the Formosan Medical... Aug 2018Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the... (Review)
Review
Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the world. The most characteristic marker of DKD is albuminuria, which is associated with renal disease progression and cardiovascular events. Renal hemodynamics changes, oxidative stress, inflammation, hypoxia and overactive renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of DKD, and renal fibrosis plays the key role. Intensified multifactorial interventions, including RAAS blockades, blood pressure and glucose control, and quitting smoking, help to prevent DKD development and progression. In recent years, novel agents are applied for preventing DKD development and progression, including new types of glucose-lowering agents, pentoxifylline, vitamin D analog paricalcitol, pyridoxamine, ruboxistaurin, soludexide, Janus kinase inhibitors and nonsteroidal minerocorticoid receptor antagonists. In this review, recent large studies about DKD are also summarized.
Topics: Albuminuria; Biomarkers; Diabetic Nephropathies; Disease Progression; Humans; Kidney Failure, Chronic; Pentoxifylline; Renin-Angiotensin System
PubMed: 29486908
DOI: 10.1016/j.jfma.2018.02.007 -
Annual Review of Pathology 2011Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the... (Review)
Review
Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor β and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney.
Topics: Diabetic Nephropathies; Humans; Kidney
PubMed: 21261520
DOI: 10.1146/annurev.pathol.4.110807.092150 -
Indian Journal of Ophthalmology Nov 2021To evaluate the presence of nephropathy and neuropathy in patients with diabetic retinopathy (DR) and to correlate the severity of DR to that of diabetic nephropathy and...
PURPOSE
To evaluate the presence of nephropathy and neuropathy in patients with diabetic retinopathy (DR) and to correlate the severity of DR to that of diabetic nephropathy and diabetic neuropathy.
METHODS
This prospective noninterventional hospital-based study included 57 consecutive cases of DR of either sex, presenting to the eye OPD between January 2019 and November 2020 with minimum 5-year duration of Type 1 and 2 DM. Complete ophthalmic examination was done and DR was classified according to early treatment diabetic retinopathy study classification. Severity of diabetic nephropathy was based on urine albumin creatinine ratio and estimated glomerular filtration rate. Severity of diabetic neuropathy was based on nerve conduction velocity.
RESULTS
The study was conducted on 57 patients of whom patients 45 were males and 12 were females. Mild nonproliferative diabetic retinopathy was present in 22 patients, moderate in 14 patients, severe in 18 patients, and proliferative diabetic retinopathy in 3 patients. In our study, group 30 patients of DR presented without clinically significant macular edema (CSME) and 27 patients presented with CSME. The distribution of severity of DR according to CSME was observed to be statistically significant (P<<0.05). The association of severity of DR with severity of diabetic nephropathy was observed to be statistically significant (P<<0.05). The association of severity of DR with that of diabetic neuropathy was inconclusive.
CONCLUSION
The association of severity of DR with severity of diabetic nephropathy and diabetic neuropathy can be used as a marker for future chronic kidney diseases progression and also to prognosticate neurological outcomes in diabetic patients.
Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Humans; Macular Edema; Male; Prospective Studies; Risk Factors
PubMed: 34708806
DOI: 10.4103/ijo.IJO_1237_21 -
Biomedicine & Pharmacotherapy =... Dec 2022Diabetic nephropathy (DN) is the leading cause of end‑stage renal disease. Although Ginkgo biloba extract has a protective effect on DN, the protective effect and...
Diabetic nephropathy (DN) is the leading cause of end‑stage renal disease. Although Ginkgo biloba extract has a protective effect on DN, the protective effect and mechanism of its active ingredient Ginkgolide B (GB) on DN remain unclear. The aim of the present study was to investigate whether GB improves DN via alleviating oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination in PA-G-induced mouse podocytes and DN mice. The study in vitro showed that GB effectively reduced serum total cholesterol, triglyceride concentrations and lipid accumulation in PA-G-induced MPC5 cells. In addition, GB promoted the expression of ferroptosis markers GPX4 and FTH1, while inhibited the expression of TfR1, fibrosis markers α-SMA and Collagen α1, as well as intracellular iron content and ROS levels. Interference of GPX4 expression with siRNA counteracted the effect of GB. And GB inhibited GPX4 ubiquitination in a dose-dependent manner. In vivo the experimental results showed that GB effectively reduced hyperglycemia, serum total cholesterol and triglyceride concentrations, reduced urinary albumin excretion and the number of renal lipid droplets, and improved changes in renal structure in DN mice. GB inhibited the expression of ferroptosis marker TfR1 and fibrosis markers α-SMA and Collagen α1, while promoted the expression of ferroptosis markers GPX4 and FTH1. In conclusion, the results suggested that GB may improve DN via protecting the kidney from ferroptosis and oxidative stress damage by inhibiting the ubiquitination of GPX4. These findings suggested that GB, a natural medicine, may be an effective therapeutic option for DN.
Topics: Mice; Animals; Ferroptosis; Diabetic Nephropathies; Phospholipid Hydroperoxide Glutathione Peroxidase; Oxidative Stress; Ubiquitination; Fibrosis; Triglycerides; Cholesterol; Diabetes Mellitus
PubMed: 36411664
DOI: 10.1016/j.biopha.2022.113953 -
Frontiers in Immunology 2020Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus. It is the most frequent cause of end-stage renal disease with no definitive therapy... (Review)
Review
Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus. It is the most frequent cause of end-stage renal disease with no definitive therapy available so far. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are nano- and micron-sized heterogeneous vesicles that can be secreted by almost all cell types. Importantly, EVs contain many biologically active materials, such as RNAs, DNAs, proteins, and lipids, from their parental cells, which can be transported to their recipient cells to mediate intercellular communication and signaling. Accumulating studies demonstrated that EVs, mainly exosomes and microvesicles, participated in the pathophysiological process of DN. Recently emerging studies also found that the contents of EVs in the urine (miRNAs, mRNAs, and proteins) could be used as potential biomarkers for DN. Therefore, in this mini-review, the generation, isolation methods, and biological function of EVs were introduced, and then the current information about the mechanism and the diagnostic value in the development of DN was summarized. Moreover, the review also discussed the future challenges of exploring the role of EVs in kidney disease.
Topics: Animals; Biomarkers; Cell Communication; Diabetic Nephropathies; Extracellular Vesicles; Humans; Kidney; Signal Transduction
PubMed: 32582146
DOI: 10.3389/fimmu.2020.00943 -
Minerva Medica Jun 2018Diabetic nephropathy (DN) also named diabetic kidney disease (DN) is one of the leading causes of mortality in people with diabetes. The aim of this review is to update... (Review)
Review
Diabetic nephropathy (DN) also named diabetic kidney disease (DN) is one of the leading causes of mortality in people with diabetes. The aim of this review is to update the medical literature, the theories behind its early natural history, the pathways of its pathogenesis, its diagnosis and treatment. Poor glycemic control, hyperlipidemia, smoking, oxidative stress, accumulation of advanced glycated end products, environmental, genetic and epigenetic factors play an important role in the pathophysiological development of DN. Microalbuminuria has been traditionally used as the primary early diagnostic marker of microvascular complication unraveling the risk for progress to severe cardiorenal outcomes, but its prognostic role has been recently debated. The disease often leads to end-stage renal disease and it is often associated with major cardiovascular outcomes. Its early diagnosis is crucial for the patients in order to have a chance for proper treatment.
Topics: Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Risk Factors
PubMed: 29205998
DOI: 10.23736/S0026-4806.17.05496-9 -
Frontiers in Endocrinology 2022With the development of economy, the living standard of people all over the world has been greatly improved, and the incidence of diabetes is also increasing. Many...
BACKGROUND
With the development of economy, the living standard of people all over the world has been greatly improved, and the incidence of diabetes is also increasing. Many people with diabetes also develop other complications that reduce their quality of life. Diabetic nephropathy is a common complication of type2 diabetes. Understanding the related factors of diabetic nephropathy is greatly significant to control the occurrence of diabetic nephropathy and improve patient's life quality.
DATA AND METHODS
Data were collected from 2009 to 2018 in NHANES. Curve fitting graph was performed to investigate the association between globulin (GLB) and diabetic nephropathy(DN). Four logistic regression models were conducted to control the potential confounding factors. Subgroup analysis was carried out to assess the stability of results.
RESULTS
GLB was positively correlated with the occurrence of DN after controlling for potential confounders. Higher GLB was associated with an increased risk of diabetic nephropathy [odds ratio(OR), 1.10; 95% confidence interval (CI), 1.07-1.13, < 0.001].
CONCLUSIONS
In this cross-sectional study, GLB was significant positively correlated with the occurrence of DN in patients with type2 diabetes mellitus.
Topics: Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Globulins; Humans; Nutrition Surveys; Quality of Life
PubMed: 35898464
DOI: 10.3389/fendo.2022.890273 -
Frontiers in Endocrinology 2023A causal relationship concerning coffee intake and diabetic nephropathy (DN) is controversial. We conducted a Mendelian randomization study to assess the causal nature...
RATIONALE AND OBJECTIVE
A causal relationship concerning coffee intake and diabetic nephropathy (DN) is controversial. We conducted a Mendelian randomization study to assess the causal nature of these associations.
METHODS
40 independent single nucleotide polymorphisms (SNPs) associated with coffee intake were selected from the UK Biobank study. Summary-level data for diabetic nephropathy were obtained from publicly available genome-wide association studies (GWAS) and the FinnGen consortium. Inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods were used to examine a causal association. Sensitivity analyses included Cochran's Q test, the intercept of MR-Egger, MR-PRESSO, and the Outlier method. Leave-One-Out sensitivity analyses were also conducted to reduce the heterogeneity.
RESULTS
Our current study demonstrated positive associations of genetically predicted coffee intake with diabetic nephropathy (OR=1.939; = 0.045 and type 2 diabetes with renal complications (OR = 2.787, = 0.047). These findings were robust across several sensitivity analyses.
CONCLUSIONS
This study found a positive correlation between coffee consumption and the risk of diabetic nephropathy using genetic data. For a more accurate and trustworthy conclusion, subgroup analysis on coffee intake, including preparing method, variety of coffee, and quantity, is required.
Topics: Humans; Diabetic Nephropathies; Coffee; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Mendelian Randomization Analysis
PubMed: 37469984
DOI: 10.3389/fendo.2023.1169933 -
Nature Communications Jan 2023Statins play an important role in the treatment of diabetic nephropathy. Increasing attention has been given to the relationship between statins and insulin resistance,...
Statins play an important role in the treatment of diabetic nephropathy. Increasing attention has been given to the relationship between statins and insulin resistance, but many randomized controlled trials confirm that the therapeutic effects of statins on diabetic nephropathy are more beneficial than harmful. However, further confirmation of whether the beneficial effects of chronic statin administration on diabetic nephropathy outweigh the detrimental effects is urgently needed. Here, we find that long-term statin administration may increase insulin resistance, interfere with lipid metabolism, leads to inflammation and fibrosis, and ultimately fuel diabetic nephropathy progression in diabetic mice. Mechanistically, activation of insulin-regulated phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway leads to increased fatty acid synthesis. Furthermore, statins administration increases lipid uptake and inhibits fatty acid oxidation, leading to lipid deposition. Here we show that long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fatty Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Insulin Resistance; Lipids; Mammals
PubMed: 36693830
DOI: 10.1038/s41467-023-35944-z