Pathomechanisms of Diabetic Kidney Disease

Sinha, Satyesh K.; Nicholas, Susanne B.

doi:10.3390/jcm12237349

Cited by 15 publications

(3 citation statements)

References 397 publications

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“…Combination therapies involving two or more drugs have been found to have the potential to treat DKD. For instance, combining ERA with SGLT2 inhibitors has shown promise[ 32 ]. The present study also validated the efficacy of a herbal combination for treating DKD, providing a preliminary possibility for future exploration of new combinations of traditional Chinese medicine combined with other inhibitors and drugs for treating DKD.…”

Section: Discussionmentioning

confidence: 99%

Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification

Che,

Yuan,

Min

et al. 2024

World J Diabetes

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BACKGROUND Diabetic kidney disease (DKD) is one of the serious complications of diabetes mellitus, and the existing treatments cannot meet the needs of today's patients. Traditional Chinese medicine has been validated for its efficacy in DKD after many years of clinical application. However, the specific mechanism by which it works is still unclear. Elucidating the molecular mechanism of the Nardostachyos Radix et Rhizoma -rhubarb drug pair (NRDP) for the treatment of DKD will provide a new way of thinking for the research and development of new drugs. AIM To investigate the mechanism of the NRDP in DKD by network pharmacology combined with molecular docking, and then verify the initial findings by in vitro experiments. METHODS The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredient targets of NRDP. Targets for DKD were obtained based on the Genecards, OMIM, and TTD databases. The VENNY 2.1 database was used to obtain DKD and NRDP intersection targets and their Venn diagram, and Cytoscape 3.9.0 was used to build a "drug-component-target-disease" network. The String database was used to construct protein interaction networks. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Ontology analysis were performed based on the DAVID database. After selecting the targets and the active ingredients, Autodock software was used to perform molecular docking. In experimental validation using renal tubular epithelial cells (TCMK-1), we used the Cell Counting Kit-8 assay to detect the effect of NRDP on cell viability, with glucose solution used to mimic a hyper-glycemic environment. Flow cytometry was used to detect the cell cycle progression and apoptosis. Western blot was used to detect the protein expression of STAT3, p-STAT3, BAX, BCL-2, Caspase9, and Caspase3. RESULTS A total of 10 active ingredients and 85 targets with 111 disease-related signaling pathways were obtained for NRDP. Enrichment analysis of KEGG pathways was performed to determine advanced glycation end products (AGEs)-receptor for AGEs (RAGE) signaling as the core pathway. Molecular docking showed good binding between each active ingredient and its core targets. In vitro experiments showed that NRDP inhibited the viability of TCMK-1 cells, blocked cell cycle progression in the G0/G1 phase, and reduced apoptosis in a concentration-dependent manner. Based on the results of Western blot analysis, NRDP differentially downregulated p-STAT3, BAX, Caspase3, and Caspase9 protein levels (P < 0.01 or P < 0.05). In addition, BAX/BCL-2 and p-STAT3/STAT3 ratios were reduced, while BCL-2 and STAT3 protein expression was upregulated (P < 0.01). CONCLUSION NRDP may upregulate BCL-2 and STAT3 protein expression, and downregulate BAX, Caspase3, and Caspase9 protein expression, thus activating the AGE-RAGE signaling pathway, inhibiting the vitality of TCMK-1 cells, reducing their apoptosis. and arresting them in the G0/G1 phase to protect them from damage by high glucose.

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Section: Discussionmentioning

confidence: 99%

Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification

Che,

Yuan,

Min

et al. 2024

World J Diabetes

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“…Interestingly, in this trial there were people with both normal and increased albuminuria, as well as patients with and without DM. Accordingly, the Kidney Disease: Improving Global Outcomes (KDIGO) and American Diabetes Association (ADA) guidelines recommended the use of SGLT2i in patients with DKD and cardiovascular disease on top of the standard of care [85]. Notably, when SGLT2i were given on top of ACEI/ARB, the beneficial effect on kidney function decline was some 30-40% greater than patients receiving ACEI/ARB alone [8].…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

“…Beyond the well-known favorable action of SGLT2i on tubulo-glomerular feedback and glomerular hyperfiltration, they also exhibit pleiotropic effects. Several studies in humans and animal diabetic models showed that SGLT2i reduce inflammation, extracellular matrix turnover, and fibrosis [85].…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection

Mazzieri,

Porcellati,

Timio

et al. 2024

IJMS

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Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD.

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Effects of APOE isoforms in diabetic nephropathy patients of South India

Basavaraju,

Moorthi,

Meyyazhagan

et al. 2024

Acta Diabetol

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Background Diabetic nephropathy (DN) is a grave complication and the most common renal dysfunction of diabetes mellitus. Genetic factors, including Apolipoprotein E (APOE) isoforms, have been implicated in the pathogenesis of DN. Methods A total of 577 type 2 Diabetes mellitus subjects were categorized into diabetes non-nephropathic (Controls: n = 321), diabetes nephropathic (DN: n = 256) groups. Demographic, clinical, and biochemical parameters including age, BMI, lipid profiles (TC, LDL-C, HDL-C, TG), glucose metabolism (plasma glucose, HbA1c, serum insulin), renal function (UACR, PCR), and blood pressure (SBP, DBP) were assessed. APOE variant frequencies were determined using restriction fragment length polymorphism (RFLP) analysis, validated against Hardy-Weinberg equilibrium (HWE), and statistically correlated with each clinical and biochemical parameter. Results The DN group had an increased prevalence of hypertension, fatty liver, and dyslipidemia compared to the Control group. Biochemical analyses revealed elevated levels of TC (213.41 mg/dL vs. 189.32 mg/dL), LDL-C (134.46 mg/dL vs. 107.56 mg/dL), and reduced HDL-C (58.13 mg/dL vs. 65.32 mg/dL) in DN cases compared to Controls (all p < 0.0001). The APOE variants distribution showed a significant increase in E2 allele frequency (69.1% vs. 15.3%) and corresponding homozygous genotype (E2/2: 42.2% vs. 5.6%) in DN cohorts. Conclusion The study found a higher frequency of E2 allele in the DN group compared to Controls, though no statistically significant risk of DN was linked to this allele. The results suggest a potential association for APOE polymorphisms, requiring broader studies to clarify the role of APOE polymorphisms in DN susceptibility.

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Pathomechanisms of Diabetic Kidney Disease

Cited by 15 publications

References 397 publications

Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification

Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification

Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection

Effects of APOE isoforms in diabetic nephropathy patients of South India

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