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Frontiers in Endocrinology 2024Diabetic Nephropathy (DN) is one of the microvascular complications of diabetes. The potential targets of renin-angiotensin-aldosterone system (RAAS) inhibitors for the...
Network pharmacology combined with Mendelian randomization analysis to identify the key targets of renin-angiotensin-aldosterone system inhibitors in the treatment of diabetic nephropathy.
BACKGROUND
Diabetic Nephropathy (DN) is one of the microvascular complications of diabetes. The potential targets of renin-angiotensin-aldosterone system (RAAS) inhibitors for the treatment of DN need to be explored.
METHODS
The GSE96804 and GSE1009 datasets, 729 RAAS inhibitors-related targets and 6,039 DN-related genes were derived from the public database and overlapped with the differentially expressed genes (DN vs. normal) in GSE96804 to obtain the candidate targets. Next, key targets were screened via the Mendelian randomization analysis and expression analysis. The diagnostic nomogram was constructed and assessed in GSE96804. Additionally, enrichment analysis was conducted and a 'core active ingredient-key target-disease pathway' network was established. Finally, molecular docking was performed.
RESULTS
In total, 60 candidate targets were derived, in which and were screened as the key targets and had a causal association with DN as the protective factors ( < 0.05, OR < 1). Further, a nomogram exhibited pretty prediction efficiency. It is indicated that Benadryl hydrochloride might play a role in the DN by affecting the pathways of 'cytokine cytokine receptor interaction', etc. targeting the . Moreover, might be involved in 'ECM receptor interaction', etc. for the effect of NSAID, captopril, chlordiazepoxide on DN. Molecular docking analysis showed a good binding ability of benadryl hydrochloride and , NSAID and . , , and are causally associated with acute kidney injury.
CONCLUSION
and were identified as key targets for RAAS inhibitors in the treatment of DN, which might provide some clinical significance in helping to diagnose and treat DN. Among the targets of RAAS inhibitors, PTGS2, ITGA4 and ANPEP have a causal relationship with acute kidney injury, which is worthy of further clinical research.
Topics: Humans; Diabetic Nephropathies; Renin-Angiotensin System; Molecular Docking Simulation; Mendelian Randomization Analysis; Network Pharmacology; Cyclooxygenase 2; Acute Kidney Injury; Anti-Inflammatory Agents, Non-Steroidal; Diphenhydramine; Diabetes Mellitus
PubMed: 38332893
DOI: 10.3389/fendo.2024.1354950 -
Biomedicine & Pharmacotherapy =... Aug 2023Platelet-derived growth factors (PDGFs) are basic proteins stored in the α granules of platelets. PDGFs and their receptors (PDGFRs) are widely expressed in platelets,... (Review)
Review
Platelet-derived growth factors (PDGFs) are basic proteins stored in the α granules of platelets. PDGFs and their receptors (PDGFRs) are widely expressed in platelets, fibroblasts, vascular endothelial cells, platelets, pericytes, smooth muscle cells and tumor cells. The activation of PDGFR plays a number of critical roles in physiological functions and diseases, including normal embryonic development, cellular differentiation, and responses to tissue damage. In recent years, emerging experimental evidence has shown that activation of the PDGF/PDGFR pathway is involved in the development of diabetes and its complications, such as atherosclerosis, diabetic foot ulcers, diabetic nephropathy, and retinopathy. Research on targeting PDGF/PDGFR as a treatment has also made great progress. In this mini-review, we summarized the role of PDGF in diabetes, as well as the research progress on targeted diabetes therapy, which provides a new strategy for the treatment of type 2 diabetes.
Topics: Pregnancy; Female; Humans; Diabetes Mellitus, Type 2; Endothelial Cells; Platelet-Derived Growth Factor; Receptor, Platelet-Derived Growth Factor beta; Diabetic Nephropathies; Receptors, Platelet-Derived Growth Factor
PubMed: 37290188
DOI: 10.1016/j.biopha.2023.114983 -
Ugeskrift For Laeger May 2024Assessment and treatment of hyperglycaemia in people with diabetes and chronic kidney disease (CKD) are challenging. In advanced CKD HbA1c can be unreliable, and... (Review)
Review
Assessment and treatment of hyperglycaemia in people with diabetes and chronic kidney disease (CKD) are challenging. In advanced CKD HbA1c can be unreliable, and treatment adjustments should be supported by other glucose measurements (e.g., continuous glucose monitoring (CGM) or blood glucose measurements). Glucose-lowering treatments should be evaluated based on CKD and an individualised assessment of risk factors especially hypoglycaemia. This review aims at providing an overview of the options for glycaemic monitoring and glucose-lowering treatments in people with diabetes and CKD.
Topics: Humans; Renal Insufficiency, Chronic; Hyperglycemia; Hypoglycemic Agents; Blood Glucose; Blood Glucose Self-Monitoring; Glycated Hemoglobin; Diabetes Mellitus, Type 2; Diabetes Mellitus; Diabetic Nephropathies; Risk Factors
PubMed: 38808757
DOI: 10.61409/V01240051 -
International Journal of Molecular... Aug 2023Diabetes mellitus (DM) belongs to the category of socially significant diseases with epidemic rates of increases in prevalence. Diabetic nephropathy (DN) is a specific... (Review)
Review
Diabetes mellitus (DM) belongs to the category of socially significant diseases with epidemic rates of increases in prevalence. Diabetic nephropathy (DN) is a specific kind of kidney damage that occurs in 40% of patients with DM and is considered a serious complication of DM. Most modern methods for treatments aimed at slowing down the progression of DN have side effects and do not produce unambiguous positive results in the long term. This fact has encouraged researchers to search for additional or alternative treatment methods. Hyperglycemia has a negative effect on renal structures due to a number of factors, including the activation of the polyol and hexosamine glucose metabolism pathways, the activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, the accumulation of advanced glycation end products and increases in the insulin resistance and endothelial dysfunction of tissues. The above mechanisms cause the development of oxidative stress (OS) reactions and mitochondrial dysfunction, which in turn contribute to the development and progression of DN. Modern antioxidant therapies for DN involve various phytochemicals (food antioxidants, resveratrol, curcumin, alpha-lipoic acid preparations, etc.), which are widely used not only for the treatment of diabetes but also other systemic diseases. It has also been suggested that therapeutic approaches that target the source of reactive oxygen species in DN may have certain advantages in terms of nephroprotection from OS. This review describes the significance of studies on OS biomarkers in the pathogenesis of DN and analyzes various approaches to reducing the intensity of OS in the prevention and treatment of DN.
Topics: Humans; Antioxidants; Diabetic Nephropathies; Oxidative Stress; Reactive Oxygen Species; Kidney; Diabetes Mellitus
PubMed: 37569752
DOI: 10.3390/ijms241512378 -
Advanced Science (Weinheim,... Mar 2024Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN....
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN. Renal tubular injury triggered by ferroptosis might be essential in this process. Numerous studies demonstrate that the vitamin D receptor (VDR) exerts beneficial effects by suppressing ferroptosis. However, the underlying mechanism has not been fully elucidated. Thus, they verified the nephroprotective effect of VDR activation and explored the mechanism by which VDR activation suppressed ferroptosis in db/db mice and high glucose-cultured proximal tubular epithelial cells (PTECs). Paricalcitol (PAR) is a VDR agonist that can mitigate kidney injury and prevent renal dysfunction. PAR treatment could inhibit ferroptosis of PTECs through decreasing iron content, increasing glutathione (GSH) levels, reducing malondialdehyde (MDA) generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 (TFR-1), and enhancing the expression of negative ferroptosis mediators including ferritin heavy chain (FTH-1), glutathione peroxidase 4 (GPX4), and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Mechanistically, VDR activation upregulated the NFE2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway to suppress ferroptosis in PTECs. These findings suggested that VDR activation inhibited ferroptosis of PTECs in DN via modulating the Nrf2/HO-1 signaling pathway.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Nephropathies; Epithelial Cells; Ferroptosis; Glutathione; Heme Oxygenase-1; NF-E2-Related Factor 2; Receptors, Calcitriol; Signal Transduction
PubMed: 38145959
DOI: 10.1002/advs.202305563 -
Frontiers in Endocrinology 2024Diabetic retinopathy (DR) and diabetic nephropathy (DN), are major microvascular complications of diabetes. DR is an important predictor of DN, but the relationship...
CONTEXT
Diabetic retinopathy (DR) and diabetic nephropathy (DN), are major microvascular complications of diabetes. DR is an important predictor of DN, but the relationship between the severity of DR and the pathological severity of diabetic glomerulopathy remains unclear.
OBJECTIVE
To investigate the relationship between severity of diabetic retinopathy (DR) and histological changes and clinical indicators of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM).
METHODS
Patients with T2DM (n=272) who underwent a renal biopsy were eligible. Severity of DR was classified as non-diabetic retinopathy, non-proliferative retinopathy, and proliferative retinopathy (PDR). Relationship between DN and DR and the diagnostic efficacy of DR for DN were explored.
RESULTS
DN had a higher prevalence of DR (86.4%) and DR was more severe. The sensitivity and specificity of DR in DN were 86.4% and 78.8%, while PDR was 26.4% and 98.5%, respectively. In DN patients, the severity of glomerular lesions (p=0.001) and prevalence of KW nodules (p<0.001) significantly increased with increasing severity of DR. The presence of KW nodules, lower hemoglobin levels, and younger age were independent risk factors associated with more severe DR in patients with DN.
CONCLUSION
DR was a good predictor of DN. In DN patients, the severity of DR was associated with glomerular injury, and presence of KW nodules, lower hemoglobin levels and younger age were independent risk factors associated with more severe DR.
TRIAL REGISTRATION
ClinicalTrails.gov, NCT03865914.
Topics: Humans; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Risk Factors; Hemoglobins
PubMed: 38344659
DOI: 10.3389/fendo.2024.1292412 -
Molecular Medicine (Cambridge, Mass.) Jul 2023The kidney is an important organ for maintaining normal metabolism and stabilising the internal environment, in which, the heterogeneity of cell types has hindered the... (Review)
Review
The kidney is an important organ for maintaining normal metabolism and stabilising the internal environment, in which, the heterogeneity of cell types has hindered the progress in understanding the mechanisms underlying kidney disease. In recent years the application of single-cell RNA sequencing (scRNA-seq) in nephrology has developed rapidly. In this review, we summarized the technical platform related to scRNA-seq and the role of this technology in investigating the onset and development of kidney diseases, starting from several common kidney diseases (mainly including lupus nephritis, renal cell carcinoma, diabetic nephropathy and acute kidney injury), and provide a reference for the application of scRNA-seq in the study of kidney disease diagnosis, treatment and prognosis.
Topics: Humans; Kidney; Diabetic Nephropathies; Carcinoma, Renal Cell; Kidney Neoplasms; Sequence Analysis, RNA; Gene Expression Profiling
PubMed: 37400792
DOI: 10.1186/s10020-023-00693-8 -
Frontiers in Endocrinology 2023Diabetic nephropathy (DN) is a serious microvascular consequence of diabetes mellitus (DM), posing an encumbrance to public health worldwide. Control over the onset and... (Review)
Review
Diabetic nephropathy (DN) is a serious microvascular consequence of diabetes mellitus (DM), posing an encumbrance to public health worldwide. Control over the onset and progress of DN depend heavily on early detection and effective treatment. DN is a major contributor to end-stage renal disease, and a complete cure is yet to be achieved with currently available options. Though some therapeutic molecules have exhibited promise in treating DN complications, their poor solubility profile, low bioavailability, poor permeation, high therapeutic dose and associated toxicity, and low patient compliance apprehend their clinical usefulness. Recent research has indicated nano-systems as potential theranostic platforms displaying futuristic promise in the diagnosis and treatment of DN. Early and accurate diagnosis, site-specific delivery and retention by virtue of ligand conjugation, and improved pharmacokinetic profile are amongst the major advantages of nano-platforms, defining their superiority. Thus, the emergence of nanoparticles has offered fresh approaches to the possible diagnostic and therapeutic strategies regarding DN. The present review corroborates an updated overview of different types of nanocarriers regarding potential approaches for the diagnosis and therapy of DN.
Topics: Humans; Diabetic Nephropathies; Nanomedicine; Kidney Failure, Chronic; Glomerular Filtration Rate; Precision Medicine; Diabetes Mellitus
PubMed: 38027185
DOI: 10.3389/fendo.2023.1236686 -
International Journal of Biological... 2024TGF-β/Smad3 signaling plays a critical role in type 2 diabetes (T2D) and type 2 diabetic nephropathy (T2DN), but treatment by specifically targeting Smad3 remains...
TGF-β/Smad3 signaling plays a critical role in type 2 diabetes (T2D) and type 2 diabetic nephropathy (T2DN), but treatment by specifically targeting Smad3 remains unexplored. To develop a new Smad3-targeted therapy for T2D and T2DN, we treated db/db mice at the pre-diabetic or established diabetic stage with a pharmacological Smad3 inhibitor SIS3. The therapeutic effect and mechanisms of anti-Smad3 treatment on T2D and T2DN were investigated. We found that anti-Smad3 treatment on pre-diabetic db/db mice largely attenuated both T2D and T2DN by markedly reducing blood glucose levels, and inhibiting the elevated serum creatinine, microalbuminuria, and renal fibrosis and inflammation. Unexpectedly, although SIS3 treatment on the established diabetic db/db mice inhibited T2DN but did not significantly improve T2D. Mechanistically, we uncovered that inhibition of T2DN in SIS3-treated db/db mice was associated with effectively restoring the balance of TGF-β/Smad signaling by inhibiting Smad3 while increasing Smad7, thereby suppressing Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation via lncRNA Erbb4-IR and LRN9884-dependent mechanisms. We also revealed that inhibition of islet β cell injury by preventing the loss of islet Pax 6 could be the mechanism through which the pre-diabetic treatment, rather than the late SIS3 treatment on db/db mice significantly improved the T2D phenotype.
Topics: Mice; Animals; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Prediabetic State; Inflammation; Transforming Growth Factor beta; Fibrosis; Smad3 Protein; Kidney
PubMed: 38164169
DOI: 10.7150/ijbs.87820 -
Frontiers in Endocrinology 2024Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes of end-stage renal disease... (Review)
Review
Diabetic nephropathy (DN) and diabetic retinopathy (DR), as microvascular complications of diabetes mellitus, are currently the leading causes of end-stage renal disease (ESRD) and blindness, respectively, in the adult working population, and they are major public health problems with social and economic burdens. The parallelism between the two in the process of occurrence and development manifests in the high overlap of disease-causing risk factors and pathogenesis, high rates of comorbidity, mutually predictive effects, and partial concordance in the clinical use of medications. However, since the two organs, the eye and the kidney, have their unique internal environment and physiological processes, each with specific influencing molecules, and the target organs have non-parallelism due to different pathological changes and responses to various influencing factors, this article provides an overview of the parallelism and non-parallelism between DN and DR to further recognize the commonalities and differences between the two diseases and provide references for early diagnosis, clinical guidance on the use of medication, and the development of new drugs.
Topics: Adult; Humans; Diabetic Nephropathies; Diabetic Retinopathy; Kidney; Kidney Failure, Chronic; Diabetes Mellitus
PubMed: 38419958
DOI: 10.3389/fendo.2024.1336123