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Cell Death & Disease Jun 2024Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role... (Review)
Review
Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role in substance metabolism via oxidative phosphorylation to generate ATP. Cells undergo metabolic reprogramming as a compensatory mechanism to fulfill energy needs for survival and growth, attracting scholarly attention in recent years. Studies indicate that mitochondrial metabolic reprogramming significantly influences the pathophysiological progression of DKD. Alterations in kidney metabolism lead to abnormal expression of signaling molecules and activation of pathways, inducing oxidative stress-related cellular damage, inflammatory responses, apoptosis, and autophagy irregularities, culminating in renal fibrosis and insufficiency. This review delves into the impact of mitochondrial metabolic reprogramming on DKD pathogenesis, emphasizing the regulation of metabolic regulators and downstream signaling pathways. Therapeutic interventions targeting renal metabolic reprogramming can potentially delay DKD progression. The findings underscore the importance of focusing on metabolic reprogramming to develop safer and more effective therapeutic approaches.
Topics: Humans; Diabetic Nephropathies; Mitochondria; Animals; Signal Transduction; Oxidative Stress; Kidney; Metabolic Reprogramming
PubMed: 38910210
DOI: 10.1038/s41419-024-06833-0 -
Iranian Journal of Kidney Diseases May 2024Diabetic nephropathy is one of the most common severe symptoms of diabetes mellitus. Hyperglycemia can lead to tissue damage and inflammation due to mediators such as...
Association Between the G82S Polymorphism of the Receptor Gene for Advanced Glycation End-products and Soluble Serum Levels RAGE with Diabetic Nephropathy in the White (Asian) Race.
INTRODUCTION
Diabetic nephropathy is one of the most common severe symptoms of diabetes mellitus. Hyperglycemia can lead to tissue damage and inflammation due to mediators such as receptor for advanced glycation end-products (RAGE). Therefore, in this study, we aimed to investigate the association between the G82S polymorphism of the RAGE gene and diabetic nephropathy in diabetic patients.
METHODS
In this case-control study, 356 participants (158 men and 198 women) of Asian race, aged 45 to 65 years, who were diagnosed with type 2 diabetes mellitus based on their fasting plasma glucose levels were enrolled. DNA was isolated from the participants' blood samples and genotyped using TETRA -Primer ARMS-PCR. Serum protein concentration of soluble RAGE (sRAGE) was also determined by enzyme-linked immunosorbent assay (ELISA).
RESULTS
Although we found differences in genotyping of participants between homozygous AA and GG and heterozygous GA in the studied groups, the differences were not significant (P = .568). In addition, we found no significant correlation between the G82S polymorphism of RAGE and the development of diabetic nephropathy. Serum levels of sRAGE were only slightly decreased in patients with diabetic nephropathy compared with diabetic patients (P > .05).
CONCLUSION
The results of this study indicate no significant association between the G82S polymorphism in the gene RAGE and the development of diabetic nephropathy. Serum levels of sRAGE were only slightly decreased in patients with diabetic nephropathy compared to diabetic patients without nephropathy. Therefore, the study suggests that there is probably no association between the G82S polymorphism in the gene RAGE and the development of diabetic nephropathy. DOI: 10.52547/ijkd.7872.
Topics: Aged; Female; Humans; Male; Middle Aged; Asian People; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Genetic Predisposition to Disease; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptor for Advanced Glycation End Products
PubMed: 38904338
DOI: 10.52547/wngvvr19 -
Iranian Journal of Kidney Diseases May 2024Diabetic nephropathy (DN) belongs to the major cause of end-stage kidney disease. We probed the functions of a microRNA miR-33a in inducing podocytes injury during...
INTRODUCTION
Diabetic nephropathy (DN) belongs to the major cause of end-stage kidney disease. We probed the functions of a microRNA miR-33a in inducing podocytes injury during childhood DN (CDN).
METHODS
Kidney samples were collected from 20 children with DN. Matrix deposition and glomerular basement membranes thickness were examined by periodic acid-Schiff staining. Immunofluorescence staining was performed to assess kidney function-related proteins. MicroRNA (MiR)-33a mimic together with miR-33a inhibitor was transfected into podocytes for determining the roles of miR-33a. Glomerular podocyte apoptosis was determined by terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining along with flow cytometry.
RESULTS
Down-regulation of Nephrin and Podocin and increased podocyte apoptosis rate were observed in the glomerulus of CDN as well as podocytes treated with high glucose. MiR-33a was up regulated in the glomeruli and glucose-treated podocytes. Injury in podocytes was aggravated with miR-33a elevation but alleviated with miR-33a inhibition. Moreover, the expression of Sirtuin 6 (Sirt6) was decreased while the levels of notch receptor 1 (Notch1) and notch receptor 4 (Notch4) were elevated in the glomerulus and glucose-treated podocytes. Decreased level of Sirt6 upon glucose treatment was abrogated by miR-33a inhibition, and the podocytes injury induced by glucose exposure was relieved by Sirt6 via Notch signaling.
CONCLUSION
These findings indicated that miR-33a promoted podocyte injury via targeting Sirt6-dependent Notch signaling in CDN, which might provide a novel sight for CDN treatment. DOI: 10.52547/ijkd.7904.
Topics: MicroRNAs; Diabetic Nephropathies; Podocytes; Humans; Signal Transduction; Sirtuins; Apoptosis; Male; Child; Membrane Proteins; Female; Receptors, Notch; Intracellular Signaling Peptides and Proteins; Glucose; Up-Regulation; Receptor, Notch1; Down-Regulation
PubMed: 38904337
DOI: 10.52547/g7kbp983 -
Frontiers in Endocrinology 2024
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Body Mass Index; Body Weight; Risk Factors
PubMed: 38904037
DOI: 10.3389/fendo.2024.1416865 -
Frontiers in Pharmacology 2024Diabetic nephropathy (DN) is known as the most common complication of diabetes, resulting from a complex inheritance-environment interaction without effective clinical...
Diabetic nephropathy (DN) is known as the most common complication of diabetes, resulting from a complex inheritance-environment interaction without effective clinical treatments. Herein, we revealed the protective effects and mechanisms of Zn(II)-curcumin, a curcumin derivative, against streptozotocin-induced DN in rats in the presence or absence of cadmium exposure. The present study focused on investigating the therapy of Zn(II)-curcumin against cadmium-aggravated DN by regulating gut microbiota, metabolism, inflammation and zinc homeostasis based on pathological changes, TLR4/NF-κB signaling pathway, inductively coupled plasma-mass spectrometry (ICP-MS), 16S rRNA gene sequencing and gas chromatography-mass spectrometer (GC-MS). We found Zn(II)-curcumin significantly mitigated the cadmium-aggravated phenotypes of diabetic nephropathy, as indicated by the remission of renal dysfunction, pathological changes, inflammation and zinc dyshomeostasis in streptozotocin-treated rats exposed to cadmium. Administration of Zn(II)-curcumin significantly alleviated the dysbiosis of gut microbiota and the changes of serum metabolite profiles in rats treated with streptozotocin in combination with cadmium. Notably, fecal microbial transplantation identified the ability of Zn(II)-curcumin to regulate renal function, inflammation and zinc homeostasis was partly dependent on the gut microbiota. These findings revealed that Zn(II)-curcumin alleviated cadmium-aggravated diabetic nephropathy by reshaping the gut microbiota and zinc homeostasis, which provided unique insights into the mechanisms of the treatment and prevention of diabetic nephropathy.
PubMed: 38903987
DOI: 10.3389/fphar.2024.1411230 -
Journal of Advanced Pharmaceutical... 2024Diabetes mellitus is a chronic condition defined by elevated blood sugar levels (hyperglycemia). This condition can lead to complications such as nephropathy, which is...
Diabetes mellitus is a chronic condition defined by elevated blood sugar levels (hyperglycemia). This condition can lead to complications such as nephropathy, which is histologically shown with glomerulosclerosis. Glucomannan, a component of , offers numerous health benefits, but its direct therapeutic effect on glomeruli remains uncertain. Male Wistar rats which were taken with random sampling ( = 30) were distributed into six distinct groups. All groups, excluding Group N, received 125 mg/kg BW single intraperitoneal dose of alloxan. Group N received a single dose of PBS 125 mg/kg BW. After 7 days, Group K + was induced with acarbose at a dose of 50 mg/70 kg BW (adjusted using a factor of 0.018) orally per day. Groups N and K - induced with 1% CMC Na at 0.2 mL/0.1 kg orally per day. While Group P1, P2, and P3 were orally given ethanolic extract orally per day at a dose of 100, 200, and 400 mg/kg BW. The following 50 days of treatment, the Wistar rats were euthanized, and their kidney was preserved for histological slides that were stained with hematoxylin and eosin. The oral administration of ethanolic extract in alloxan-induced diabetic rats led to a significant decrease in the average of glomerulosclerosis instances when compared to the K - group. The most effective dose was observed at 400 mg/kg BW per day. administration leads to a reduction in glomerulosclerosis occurrences, suggesting its potential as a therapeutic approach for reducing complications probability linked to hyperglycemia.
PubMed: 38903556
DOI: 10.4103/JAPTR.JAPTR_426_23 -
Nutrition & Diabetes Jun 2024Dietary-resistant starch is emerging as a potential therapeutic tool to limit the negative effects of diabetes on the kidneys. However, its metabolic and...
BACKGROUND
Dietary-resistant starch is emerging as a potential therapeutic tool to limit the negative effects of diabetes on the kidneys. However, its metabolic and immunomodulatory effects have not yet been fully elucidated.
METHODS
Six-week-old db/db mice were fed a diet containing 12.5% resistant starch or a control diet matched for equivalent regular starch for 10 weeks. db/m mice receiving the control diet were utilised as non-diabetic controls. Freshly collected kidneys were digested for flow cytometry analysis of immune cell populations. Kidney injury was determined by measuring albuminuria, histology, and immunohistochemistry. Portal vein plasma was collected for targeted analysis of microbially-derived metabolites. Intestinal histology and tight junction protein expression were assessed.
RESULTS
Resistant starch limited the development of albuminuria in db/db mice. Diabetic db/db mice displayed a decline in portal vein plasma levels of acetate, propionate, and butyrate, which was increased with resistant starch supplementation. Diabetic db/db mice receiving resistant starch had a microbially-derived metabolite profile similar to that of non-diabetic db/m mice. The intestinal permeability markers lipopolysaccharide and lipopolysaccharide binding protein were increased in db/db mice consuming the control diet, which was not seen in db/db mice receiving resistant starch supplementation. Diabetes was associated with an increase in the kidney neutrophil population, neutrophil activation, number of C5aR1+ neutrophils, and urinary complement C5a excretion, all of which were reduced with resistant starch. These pro-inflammatory changes appear independent of fibrotic changes in the kidney.
CONCLUSIONS
Resistant starch supplementation in diabetes promotes beneficial circulating microbially-derived metabolites and improves intestinal permeability, accompanied by a modulation in the inflammatory profile of the kidney including neutrophil infiltration, complement activation, and albuminuria. These findings indicate that resistant starch can regulate immune and inflammatory responses in the kidney and support the therapeutic potential of resistant starch supplementation in diabetes on kidney health.
Topics: Animals; Mice; Kidney; Albuminuria; Male; Neutrophil Infiltration; Diabetic Nephropathies; Resistant Starch; Gastrointestinal Microbiome; Starch; Diabetes Mellitus, Experimental; Mice, Inbred C57BL
PubMed: 38902253
DOI: 10.1038/s41387-024-00305-2 -
BMJ Open Diabetes Research & Care Jun 2024The overall aim of this study was to evaluate the implementation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients in tertiary care with type 2...
INTRODUCTION
The overall aim of this study was to evaluate the implementation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients in tertiary care with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).
RESEARCH DESIGN AND METHODS
The cross-sectional analysis was based on outpatients in tertiary diabetes care enrolled in the Swiss Diabetes Registry with T2DM and a study visit January 1, 2020-March 31, 2021. Prevalence of CKD was ascertained as an estimated glomerular filtration rate <60 mL/min/1.73 m and/or persistent albuminuria as defined by Kidney Disease Improving Global Outcomes, and the proportion of patients prescribed SGLT2i was determined. Documented reasons for non-treatment with SGLT2i were extracted by a retrospective review of the medical records.
RESULTS
Of 368 patients with T2DM, 1.1% (n=4) were excluded due to missing data. Of the remaining 364 patients, 47.3% (n=172) had CKD of which 32.6% (n=56) were prescribed SGLT2i. The majority (75%) of these patients were on treatment already in 2018, before the renoprotective effects of SGLT2i were established. Among the 116 patients without SGLT2i, 19.0% had known contraindications, 9.5% stopped treatment due to adverse events, 5.2% had other reasons, and no underlying reason for non-treatment could be identified for 66.4%.
CONCLUSIONS
A divergence between recommended standard of care and implementation in daily clinical practice was observed. Although treatment should always consider patient-specific circumstances, the results highlight the need to reinforce current treatment recommendations to ensure patients benefit from the best available care.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Female; Male; Renal Insufficiency, Chronic; Cross-Sectional Studies; Middle Aged; Aged; Glomerular Filtration Rate; Tertiary Healthcare; Retrospective Studies; Switzerland; Registries; Diabetic Nephropathies; Prognosis; Follow-Up Studies
PubMed: 38901857
DOI: 10.1136/bmjdrc-2024-004108 -
Kidney & Blood Pressure Research Jun 2024The early diagnosis of kidney injury in type 2 diabetes (T2DM) is important to prevent the long-term damaging effects of kidney loss and is decisive for patient...
INTRODUCTION
The early diagnosis of kidney injury in type 2 diabetes (T2DM) is important to prevent the long-term damaging effects of kidney loss and is decisive for patient outcomes. While SIRT2 is implicated in diabetes pathogenesis, its correlation with diabetic nephropathy remains unexplored. This study was designed to evaluate the association of circulating and urine SIRT2 levels with diabetic kidney injury, as well as potential underlying mechanisms.
METHODS
In T2DM patients, db/db mice, and high-glucose plus palmitic acid treated HK-2 cell models, ELISA, immunoturbidimetry, immunohistochemistry, western blot and RT-qPCR were used to detect SIRT2 levels and kidneys damage. According to urinary albumin/creatinine ratio (UACR), 163 T2DM patients were divided into three groups. Spearman correlation analysis was used to investigate the relationship between urinary sirtuin2/creatinine ratio (USCR) and biomarkers of kidney injury. The influencing factors of proteinuria in T2DM patients were analyzed by Logistic regression model.
RESULTS
In our findings, the Macro group exhibited the highest USCR levels as UACR increased. There was a positive association between USCR and UACR, α1-microglobulin/creatinine ratio (UαCR), β2-microglobulin/creatinine ratio (UβCR), and retinol-binding protein/creatinine ratio (URCR), with a negative correlation observed with eGFR. Logistic ordered multiclassification regression analysis, adjusting for confounding variables, confirmed that USCR remained a significant risk factor for the severity of proteinuria in T2DM patients. In the kidney tissue of db/db mice, increased KIM-1 levels were associated with increased SIRT2 levels. Increased SIRT2 protein levels were also observed in renal tubular epithelial cells treated with high-glucose plus palmitic acid. Moreover, SIRT2 promotes the expression of pro-inflammatory factors TNF-α and IL-6 by modulating the phosphorylation of p38 MAPK and pJNK in renal tubular cells induced by high glucose and palmitic acid.
CONCLUSION
Urinary SIRT2 is closely related to eGFR, renal tubule injury and urinary albumin excretion in T2DM patients, which is expected to be an important indicator to comprehensively reflect renal injury.
PubMed: 38901411
DOI: 10.1159/000539886 -
Biomedicine & Pharmacotherapy =... Jun 2024Astragaloside IV (AS-IV) exhibits diverse biological activities. Despite this, the detailed molecular mechanisms by which AS-IV ameliorates diabetic nephropathy (DN) and...
Phenylsulfate-induced oxidative stress and mitochondrial dysfunction in podocytes are ameliorated by Astragaloside IV activation of the SIRT1/PGC1α /Nrf1 signaling pathway.
Astragaloside IV (AS-IV) exhibits diverse biological activities. Despite this, the detailed molecular mechanisms by which AS-IV ameliorates diabetic nephropathy (DN) and shields podocytes from oxidative stress (OS) and mitochondrial dysfunction remain poorly understood. In this study, we used biochemical assays, histopathological analysis, Doppler ultrasound, transmission electron microscopy,flow cytometry, fluorescence staining, and Western blotting and other methods. AS-IV was administered to db/db mice for in vivo experimentation. Our findings indicated that AS-IV treatment significantly reduced diabetes-associated markers, proteinuria, and kidney damage. It also diminished ROS levels in the kidney, enhanced the expression of endogenous antioxidant enzymes, and improved mitochondrial health. Phenyl sulfate (PS), a protein-bound uremic solute of enteric origin, has been closely linked with DN and represents a promising avenue for further research. In vitro, PS exposure induced OS and mitochondrial dysfunction in podocytes, increasing ROS levels while decreasing antioxidant enzyme activity (Catalase, Heme Oxygenase-1, Superoxide Dismutase, and Glutathione Peroxidase). ROS inhibitors (N-acetyl-L-cysteine, NAC) as the positive control group can significantly reduce the levels of ROS and restore antioxidant enzymes protein levels. Additionally, PS reduced markers associated with mitochondrial biosynthesis and function (SIRT1, PGC1α, Nrf1, and TFAM). These adverse effects were partially reversed by AS-IV treatment. However, co-treatment with AS-IV and the SIRT1 inhibitor EX527 failed to restore these indicators. Overall, our study demonstrates that AS-IV effectively attenuates DN and mitigates PS-induced OS and mitochondrial dysfunction in podocytes via the SIRT1/PGC1α/Nrf1 pathway.
PubMed: 38901196
DOI: 10.1016/j.biopha.2024.117008