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Aging Nov 2023The current study aims to understand the mechanisms behind regulated cell death (RCD) in diabetic nephropathy and identify related biomarkers through bioinformatics and...
The current study aims to understand the mechanisms behind regulated cell death (RCD) in diabetic nephropathy and identify related biomarkers through bioinformatics and experimental validation. Datasets of bulk and single-cell RNA sequencing were obtained from public databases and analyzed using gene set variation analysis (GSVA) with gene sets related to RCD, including autophagy, necroptosis, pyroptosis, apoptosis, and ferroptosis. RCD-related gene biomarkers were identified using weighted gene correlation network analysis (WGCNA). The results were verified through experiments with an independent cohort and experiments. The GSVA revealed higher necroptosis scores in diabetic nephropathy. Three necroptosis-related biomarkers, EGF, PAG1, and ZFP36, were identified and showed strong diagnostic ability for diabetic kidney disease. experiments showed high levels of necroptotic markers in HK-2 cells treated with high glucose. Bioinformatics and experimental validation have thus identified EGF and PAG1 as necroptosis-related biomarkers for diabetic nephropathy.
Topics: Humans; Necroptosis; Diabetic Nephropathies; Epidermal Growth Factor; Regulated Cell Death; Biomarkers; Diabetes Mellitus; Membrane Proteins; Adaptor Proteins, Signal Transducing
PubMed: 37988198
DOI: 10.18632/aging.205233 -
Frontiers in Endocrinology 2023The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the... (Review)
Review
The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.
Topics: Humans; Diabetic Nephropathies; Vasopressins; Receptors, Vasopressin; Renal Insufficiency, Chronic; Glucose; Diabetes Mellitus
PubMed: 37790608
DOI: 10.3389/fendo.2023.1176199 -
Biomedicine & Pharmacotherapy =... Sep 2023Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK)...
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase β (CaMKKβ) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.
Topics: Mice; Humans; Animals; Diabetic Nephropathies; AMP-Activated Protein Kinases; Chalcone; Chalcones; Diabetes Mellitus, Experimental; Calcium; Molecular Docking Simulation; Mice, Inbred C57BL; Mice, Inbred Strains; Hyperglycemia
PubMed: 37473685
DOI: 10.1016/j.biopha.2023.115158 -
Environmental Health : a Global Access... Jan 2024Cadmium (Cd) and lead (Pb) exhibit nephrotoxic activity and may accelerate kidney disease complications in diabetic patients, but studies investigating the relation to...
BACKGROUND
Cadmium (Cd) and lead (Pb) exhibit nephrotoxic activity and may accelerate kidney disease complications in diabetic patients, but studies investigating the relation to diabetic kidney disease (DKD) have been limited. We aimed to examine the associations of Cd and Pb with DKD in diabetic patients.
METHODS
3763 adults with blood metal measurements and 1604 adults with urinary ones who were diabetic from National Health and Nutrition Examination Survey (NHANES) 2007-2016 were involved. Multivariate logistic regression models were used to analyze the associations of blood Cd (BCd), blood Pb (BPb), urinary Cd (UCd), and urinary Pb (UPb) with DKD.
RESULTS
BPb, BCd, and UCd levels were higher among participants with DKD than diabetics without nephropathy, but UPb performed the opposite result. BPb and UCd were significantly associated with DKD in the adjusted models (aOR, 1.17 (1.06, 1.29);1.52 (1.06, 2.02)). Participants in the 2nd and 3rd tertiles of BPb and BCd levels had higher odds of DKD, with a significant trend across tertiles, respectively (all P-trend < 0.005). Multiplication interaction was also identified for BPb and BCd (P for interaction = 0.044).
CONCLUSION
BPb, BCd, and UCd were positively associated with the risk of DKD among diabetic patients. Furthermore, there were the dose-response relationship and multiplication interaction in the associations of BPb, BCd with DKD.
Topics: Adult; Humans; Cadmium; Environmental Exposure; Diabetic Nephropathies; Nutrition Surveys; Lead; Diabetes Mellitus
PubMed: 38166936
DOI: 10.1186/s12940-023-01045-z -
Biomedicine & Pharmacotherapy =... Sep 2023Diabetic nephropathy (DN) is one of the main complications of diabetes. However, effective therapy to block or slow down the progression of DN is still lacking....
Diabetic nephropathy (DN) is one of the main complications of diabetes. However, effective therapy to block or slow down the progression of DN is still lacking. San-Huang-Yi-Shen capsule (SHYS) has been shown to significantly improve renal function and delay the progression of DN. However, the mechanism of SHYS on DN is still unclear. In this study, we established a mouse model of DN. Then, we investigated the anti-ferroptotic effects of SHYS including the reduction of iron overload and the activation of cystine/GSH/GPX4 axis. Finally, we used a GPX4 inhibitor (RSL3) and ferroptosis inhibitor (ferrostatin-1) to determine whether SHYS ameliorates DN through inhibiting ferroptosis. The results showed that SHYS treatment was effective for mice with DN in terms of improving renal function, and reducing inflammation and oxidative stress. Besides, SHYS treatment reduced iron overload and upregulated the expression of cystine/GSH/GPX4 axis-related factors in kidney. Moreover, SHYS exhibited similar therapeutic effect on DN as ferrostatin-1, RSL3 could abolish the therapeutic and anti- ferroptotic effects of SHYS on DN. In conclusion, SHYS can be used to treat mice with DN. Furthermore, SHYS could inhibit ferroptosis in DN through reducing iron overload and upregulating the expression of cystine/GSH/GPX4 axis.
Topics: Animals; Mice; Diabetic Nephropathies; Cystine; Ferroptosis; Iron Overload; Diabetes Mellitus
PubMed: 37418978
DOI: 10.1016/j.biopha.2023.115086 -
Frontiers in Endocrinology 2024Diabetes is a metabolic disease characterized by hyperglycemia, which induces the production of AGEs, ROS, inflammatory cytokines, and growth factors, leading to the... (Review)
Review
Diabetes is a metabolic disease characterized by hyperglycemia, which induces the production of AGEs, ROS, inflammatory cytokines, and growth factors, leading to the formation of vascular dysfunction and target organ damage, promoting the development of diabetic complications. Diabetic nephropathy, retinopathy, and cardiomyopathy are common complications of diabetes, which are major contributors to disability and death in people with diabetes. Long non-coding RNAs affect gene transcription, mRNA stability, and translation efficiency to influence gene expression for a variety of biological functions. Over the past decade, it has been demonstrated that dysregulated long non-coding RNAs are extensively engaged in the pathogenesis of many diseases, including diabetic complications. Thus, this review discusses the regulations of long non-coding RNAs on the primary pathogenesis of diabetic complications (oxidative stress, inflammation, fibrosis, and microvascular dysfunction), and some of these long non-coding RNAs may function as potential biomarkers or therapeutic targets for diabetic complications.
Topics: Humans; RNA, Long Noncoding; Diabetes Complications; Diabetic Nephropathies; Hyperglycemia; Cytokines; Diabetes Mellitus
PubMed: 38390204
DOI: 10.3389/fendo.2024.1324393 -
Frontiers in Endocrinology 2024Diabetic nephropathy (DN) represents a significant microvascular complication in diabetes, entailing intricate molecular pathways and mechanisms associated with...
Diabetic nephropathy (DN) represents a significant microvascular complication in diabetes, entailing intricate molecular pathways and mechanisms associated with cardiorenal vascular diseases. Prolonged hyperglycemia induces renal endothelial dysfunction and damage via metabolic abnormalities, inflammation, and oxidative stress, thereby compromising hemodynamics. Concurrently, fibrotic and sclerotic alterations exacerbate glomerular and tubular injuries. At a macro level, reciprocal communication between the renal microvasculature and systemic circulation establishes a pernicious cycle propelling disease progression. The current management approach emphasizes rigorous control of glycemic levels and blood pressure, with renin-angiotensin system blockade conferring renoprotection. Novel antidiabetic agents exhibit renoprotective effects, potentially mediated through endothelial modulation. Nonetheless, emerging therapies present novel avenues for enhancing patient outcomes and alleviating the disease burden. A precision-based approach, coupled with a comprehensive strategy addressing global vascular risk, will be pivotal in mitigating the cardiorenal burden associated with diabetes.
Topics: Humans; Diabetic Nephropathies; Renin-Angiotensin System; Hypoglycemic Agents; Hyperglycemia; Blood Pressure; Diabetes Mellitus
PubMed: 38455648
DOI: 10.3389/fendo.2024.1368481 -
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 -
Frontiers in Endocrinology 2023Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes and is a chronic progressive condition. It is also a common cause of end-stage renal... (Review)
Review
Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes and is a chronic progressive condition. It is also a common cause of end-stage renal disease (ESRD), which is characterized by proteinuria or a progressive decline in the glomerular filtration rate. Due to their dependence on high-energy and aerobic metabolism, renal tubules are more susceptible to the metabolic disturbances associated with DKD, leading to inflammation and fibrosis. Consequently, tubular injury has become a recent research focus, and significant advancements have been made in studying the role of extracellular vesicles in DKD-associated tubular injury. This review aimed to elucidate the mechanisms and potential applications of different types of extracellular vesicles in tubular injury in DKD to provide new insights for the prevention and treatment of DKD.
Topics: Humans; Diabetic Nephropathies; Kidney Failure, Chronic; Kidney Tubules; Extracellular Vesicles; Glomerular Filtration Rate; Diabetes Mellitus
PubMed: 37732129
DOI: 10.3389/fendo.2023.1257430 -
Molecular Medicine Reports Nov 2023Diabetic nephropathy is one of the most significant complications of diabetes, resulting in increased patient mortality. Dapagliflozin is an inhibitor of...
Diabetic nephropathy is one of the most significant complications of diabetes, resulting in increased patient mortality. Dapagliflozin is an inhibitor of sodium‑glucose cotransporter 2 that has an important protective effect on the kidney. Recent studies showed that pyroptosis is involved in the advancement of diabetic nephropathy (DN). However, the potential molecular mechanisms underlying the association between pyroptosis and renal podocyte injury in DN remain unclear. Thus, the present study investigated the anti‑pyroptotic function of dapagliflozin in podocytes and further clarified the potential mechanisms. In this study, a model of lipid metabolism disturbance was established through palmitic acid (PA) induction in a mouse podocyte clone 5 (MPC5) cell line. MPC5 PA‑induced pyroptosis was measured by ELISA, western blotting, quantitative PCR and Hoechst 33342/propidium iodide double‑fluorescence staining. The protective role of HO‑1 was measured using knockdown and overexpression experiments. It was found that dapagliflozin attenuated the expression of pyroptosis‑related proteins, including nucleotide oligomerization domain‑like receptor thermal protein domain associated protein 3, apoptosis‑associated speck‑like protein containing a caspase activation and recruitment domain, caspase‑1, IL‑18 and IL‑1β in the PA group. Meanwhile, the heme oxygenase 1 (HO‑1) expression level decreased within PA, an effect that was reversed by dapagliflozin. Furthermore, the expression of pyroptosis‑related proteins and inflammatory cytokines was reduced following HO‑1 overexpression. Therefore, these results suggested that dapagliflozin ameliorates MPC5 pyroptosis by mediating HO‑1, which has a protective effect on diabetic nephropathy.
Topics: Animals; Mice; Diabetic Nephropathies; Pyroptosis; Heme Oxygenase-1; NLR Family, Pyrin Domain-Containing 3 Protein; Podocytes; Kidney
PubMed: 37711056
DOI: 10.3892/mmr.2023.13087