-
Frontiers in Endocrinology 2023Diabetic nephropathy (DN) is a complication of diabetes mellitus (DM) and the main cause of excess mortality in patients with type 2 DM. The pathogenesis and progression... (Review)
Review
Diabetic nephropathy (DN) is a complication of diabetes mellitus (DM) and the main cause of excess mortality in patients with type 2 DM. The pathogenesis and progression of DN are closely associated with disorders of glucose and lipid metabolism. As a member of the sirtuin family, SIRT6 has deacetylation, defatty-acylation, and adenosine diphosphate-ribosylation enzyme activities as well as anti-aging and anticancer activities. SIRT6 plays an important role in glucose and lipid metabolism and signaling, especially in DN. SIRT6 improves glucose and lipid metabolism by controlling glycolysis and gluconeogenesis, affecting insulin secretion and transmission and regulating lipid decomposition, transport, and synthesis. Targeting SIRT6 may provide a new therapeutic strategy for DN by improving glucose and lipid metabolism. This review elaborates on the important role of SIRT6 in glucose and lipid metabolism, discusses the potential of SIRT6 as a therapeutic target to improve glucose and lipid metabolism and alleviate DN occurrence and progression of DN, and describes the prospects for future research.
Topics: Humans; Glucose; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Lipids; Sirtuins
PubMed: 37876546
DOI: 10.3389/fendo.2023.1244705 -
Redox Biology Oct 2023Peroxisomes are metabolically active organelles that are known for exerting oxidative metabolism, but the precise mechanism remains unclear in diabetic nephropathy (DN)....
Peroxisomes are metabolically active organelles that are known for exerting oxidative metabolism, but the precise mechanism remains unclear in diabetic nephropathy (DN). Here, we used proteomics to uncover a correlation between the antioxidant protein disulfide-bond A oxidoreductase-like protein (DsbA-L) and peroxisomal function. In vivo, renal tubular injury, oxidative stress, and cell apoptosis in high-fat diet plus streptozotocin (STZ)-induced diabetic mice were significantly increased, and these changes were accompanied by a "ghost" peroxisomal phenotype, which was further aggravated in DsbA-L-deficient diabetic mice. In vitro, the overexpression of DsbA-L in peroxisomes could improve peroxisomal phenotype and function, reduce oxidative stress and cell apoptosis induced by high glucose (HG, 30 mM) and palmitic acid (PA, 250 μM), but this effect was reversed by 3-Amino-1,2,4-triazole (3-AT, a catalase inhibitor). Mechanistically, DsbA-L regulated the activity of catalase by binding to it, thereby reducing peroxisomal leakage and proteasomal degradation of peroxisomal matrix proteins induced by HG and PA. Additionally, the expression of DsbA-L in renal tubules of patients with DN significantly decreased and was positively correlated with peroxisomal function. Taken together, these results highlight an important role of DsbA-L in ameliorating tubular injury in DN by improving peroxisomal function.
Topics: Animals; Mice; Catalase; Diabetic Nephropathies; Peroxisomes; Diabetes Mellitus, Experimental; Oxidative Stress
PubMed: 37597421
DOI: 10.1016/j.redox.2023.102855 -
Frontiers in Endocrinology 2023
Topics: Humans; Kidney; Diabetic Nephropathies; Diabetes Mellitus
PubMed: 38027121
DOI: 10.3389/fendo.2023.1303514 -
Molecular Medicine (Cambridge, Mass.) Jul 2023Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease,...
BACKGROUND
Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease, and the tobacco epidemic exacerbates kidney damage in patients with DN. However, the underlying molecular mechanisms remain unclear.
METHOD
In the present study, we used a diabetic mouse model to investigate the molecular mechanisms for nicotine-exacerbated DN. Twelve-week-old female mice were injected with streptozotocin (STZ) to establish a hyperglycemic diabetic model. After four months, the control and hyperglycemic diabetic mice were further divided into four groups (control, nicotine, diabetic mellitus, nicotine + diabetic mellitus) by intraperitoneal injection of nicotine or PBS. After two months, urine and blood were collected for kidney injury assay, and renal tissues were harvested for further molecular assays using RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry. In vitro studies, we used siRNA to suppress Grem1 expression in human podocytes. Then we treated them with nicotine and high glucose to compare podocyte injury.
RESULT
Nicotine administration alone did not cause apparent kidney injury, but it significantly increased hyperglycemia-induced albuminuria, BUN, plasma creatinine, and the kidney tissue mRNA expression of KIM-1 and NGAL. Results from RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry analysis revealed that, compared to hyperglycemia or nicotine alone, the combination of nicotine treatment and hyperglycemia significantly increased the expression of Grem1 and worsened DN. In vitro experiments, suppression of Grem1 expression attenuated nicotine-exacerbated podocyte injury.
CONCLUSION
Grem1 plays a vital role in nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN.
Topics: Humans; Mice; Female; Animals; Diabetic Nephropathies; Up-Regulation; Nicotine; Diabetes Mellitus, Experimental; Hyperglycemia; Intercellular Signaling Peptides and Proteins
PubMed: 37415117
DOI: 10.1186/s10020-023-00692-9 -
International Immunopharmacology Sep 2023Proteinuria is an independent risk factor for the progression of diabetic nephropathy (DN) and an imbalance in podocyte function aggravates proteinuria. Celastrol is the...
Proteinuria is an independent risk factor for the progression of diabetic nephropathy (DN) and an imbalance in podocyte function aggravates proteinuria. Celastrol is the primary active ingredient of T. wilfordii, effective in treating DN renal injury; however, the mechanisms underlying its effect are unclear. We explored how celastrol prevents DN podocyte damage using in vivo and in vitro experiments. We randomly divided 24 male C57BLKS/J mice into three groups: db/m (n = 8), db/db (n = 8), and celastrol groups (db/db + celastrol, 1 mg/kg/d, gavage administration, n = 8). In vivo experiments lasted 12 weeks and intervention lasted ten weeks. Serum samples and kidney tissues were collected for biochemical tests, pathological staining, transmission electron microscopy, fluorescencequantitation polymerase chain reaction, and western blotting analysis. In vitro experiments to elaborate the mechanism of celastrol protection were performed on high glucose (HG)-induced podocyte injury. Celastrol reduced blood glucose levels and renal function index in db/db mice, attenuated renal histomorphological injury and glomerular podocyte foot injuries, and induced significant anti-inflammatory effects. Celastrol upregulated silent information regulator 2 related enzyme 1(SIRT1) expression and downregulated enhancer of zeste homolog (EZH2), inhibiting the wnt/β-catenin pathway-related molecules, such as wnt1, wnt7a, and β-catenin. SIRT1 repressed the promoter activity of EZH2, and was co-immunoprecipitated with EZH2 in mouse podocyte cells (MPC5). SIRT1 knockdown aggravated the protective effects of celastrol on MPC5 cells. Celastrol protected podocyte injury via SIRT1/EZH2, which participates in the wnt/β-catenin pathway. Overall, celastrol-mediated SIRT1 upregulation inhibited the EZH2-related wnt/β-catenin signaling pathway to attenuate DN and podocyte injury, providing a theoretical basis for celastrol clinical application.
Topics: Mice; Male; Animals; Diabetic Nephropathies; Wnt Signaling Pathway; beta Catenin; Sirtuin 1; Podocytes; Proteinuria; Diabetes Mellitus
PubMed: 37454630
DOI: 10.1016/j.intimp.2023.110584 -
Frontiers in Endocrinology 2024
Topics: Humans; Diabetic Retinopathy; Diabetic Nephropathies; Diabetes Mellitus, Type 2
PubMed: 38332890
DOI: 10.3389/fendo.2024.1359011 -
Frontiers in Endocrinology 2023Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has... (Review)
Review
Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD's tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.
Topics: Humans; Diabetic Nephropathies; Inflammation; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Fibrosis; Diabetes Mellitus
PubMed: 37859992
DOI: 10.3389/fendo.2023.1232790 -
Frontiers in Endocrinology 2023Bilirubin has been widely reported to be a protective factor against diabetic kidney disease (DKD) in Asian populations. However, few large-sample analyses have been...
BACKGROUND
Bilirubin has been widely reported to be a protective factor against diabetic kidney disease (DKD) in Asian populations. However, few large-sample analyses have been conducted in American populations. This study aimed to investigate the association between serum total bilirubin (STB) level and DKD in a US diabetic cohort.
METHODS
This cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Univariate and multivariate logistic regression analyses were performed to assess the association between STB level and DKD. Three models were conducted to control the potential confounding factors. Subgroup analysis was carried out for further validation.
RESULTS
Among the 5,355 participants, the median age [interquartile range (IQR)] was 62 [52-71] years; 2,836 (52.96%) were male, and 1,576 (29.43%) were diagnosed with DKD. In the entire cohort, no significant association between STB level and DKD was observed in any logistic regression models ( > 0.05). Subgroup analysis revealed that, in U.S. diabetic males, STB levels > 11.98 µmol/L were associated with a nearly 30% lower risk of DKD than STB levels ≤ 8.55 µmol/L. Additionally, a moderate STB level (8.56-11.98 μmol/L) was found associated with a nearly 25% lower risk of DKD in U.S. diabetic patients over 65 years old.
CONCLUSION
The association of STB level with DKD may depict differences across diverse populations, among which the impact of race, sex, and age requires thorough consideration and relevant inferences should be interpreted cautiously.
Topics: Humans; Male; United States; Aged; Female; Diabetic Nephropathies; Nutrition Surveys; Cross-Sectional Studies; Bilirubin; Logistic Models; Diabetes Mellitus
PubMed: 38152124
DOI: 10.3389/fendo.2023.1310003 -
Scientific Reports Sep 2023Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We...
Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We investigated the effects of galantamine on glycemic control and development of diabetic nephropathy (DN) in Lepr mice. Galantamine significantly reduced food intake, body weight, blood glucose and HbA1c levels. Insulin resistance (HOMA-IR, QUICKI), HOMA-β and elevations in plasma inflammatory cytokine levels (TNF-α, IL-6 and HMGB-1) were all attenuated by galantamine. Galantamine also ameliorated diabetes-induced kidney injury as evidenced by improvements in renal function (BUN, creatinine, albuminuria), histologic injury and apoptosis. Improved glycemic control and nephropathy were associated with increased circulating GLP-1, decreased renal P-38 MAPK and caspase-1 activation and reduced SGLT-2 expression. These findings provide insights into the mechanisms by which galantamine improves glycemic control and attenuates DN in the Lepr mouse model.
Topics: Humans; Animals; Mice; Diabetic Nephropathies; Galantamine; Acetylcholinesterase; Glycemic Control; Insulin Resistance; Receptors, Leptin; Diabetes Mellitus
PubMed: 37731032
DOI: 10.1038/s41598-023-42665-2 -
Endocrinology, Diabetes & Metabolism Nov 2023Low serum Vitamin D levels have been associated with diabetic nephropathy (DN). Our study aimed to analyse the serum levels of vitamin D in patients suffering from DN... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIM
Low serum Vitamin D levels have been associated with diabetic nephropathy (DN). Our study aimed to analyse the serum levels of vitamin D in patients suffering from DN and the subsequent changes in serum vitamin D levels as the disease progresses.
METHODS
PubMed, Embase, SCOPUS and Web of Science were searched using keywords such as '25 hydroxyvitamin D' and 'diabetic nephropathy'. We included observational studies that reported the association between the serum 25 hydroxy vitamin D levels and diabetic nephropathy without restriction to age, gender, and location. R Version 4.1.2 was used to perform the meta-analysis. The continuous outcomes were represented as mean difference (MD) and standard deviation (SD) and dichotomous outcomes as risk ratios (RR) with their 95% confidence interval (CI).
RESULTS
Twenty-three studies were included in our analysis with 7722 patients. Our analysis revealed that vitamin D was significantly lower in diabetic patients with nephropathy than those without nephropathy (MD: -4.32, 95% CI: 7.91-0.74, p-value = .0228). On comparing diabetic patients suffering from normoalbuminuria, microalbuminuria, or macroalbuminuria, we found a significant difference in serum vitamin D levels across different groups. Normoalbuminuria versus microalbuminuria showed a MD of -1.69 (95% CI: -2.28 to -1.10, p-value = .0002), while microalbuminuria versus macroalbuminuria showed a MD of (3.75, 95% CI: 1.43-6.06, p-value = .0058), proving that serum vitamin D levels keep declining as the disease progresses. Notwithstanding, we detected an insignificant association between Grade 4 and Grade 5 DN (MD: 2.29, 95% CI: -2.69-7.28, p-value = .1862).
CONCLUSION
Serum Vitamin D levels are lower among DN patients and keep declining as the disease progresses, suggesting its potential benefit as a prognostic marker. However, on reaching the macroalbuminuria stage (Grades 4 and 5), vitamin D is no longer a discriminating factor.
Topics: Humans; Diabetic Nephropathies; Vitamin D; Albuminuria; Diabetes Mellitus
PubMed: 37743677
DOI: 10.1002/edm2.453