Therapeutic Effect of Alprostadil in Diabetic Nephropathy: Possible Roles of Angiopoietin-2 and IL-18

The intrarenal renin-angiotensin system (RAS) plays a key role in the development of diabetic nephropathy. Recently, we showed that combination therapy with an AT1 receptor blocker (ARB) and an activated vitamin D analog produced excellent synergistic effects against diabetic nephropathy, as a result of blockade of the ARB-induced compensatory renin increase. Given the diversity of vitamin D analogs, here we used a pro-drug vitamin D analog, doxercalciferol (1α-hydroxyvitamin D2), to further test the efficacy of the combination strategy in long-term treatment. Streptozotocin-induced diabetic DBA/2J mice were treated with vehicle, losartan, doxercalciferol (0.4 and 0.6 μg/kg), or losartan and doxercalciferol combinations for 20 wk. Vehicle-treated diabetic mice developed progressive albuminuria and glomerulosclerosis. Losartan alone moderately ameliorated kidney injury, with renin being drastically upregulated. A similar therapeutic effect was seen with doxercalciferol alone, which markedly suppressed renin and angiotensinogen expression. The losartan and doxercalciferol combination most effectively prevented albuminuria, restored glomerular filtration barrier structure, and dramatically reduced glomerulosclerosis in a dose-dependent manner. These effects were accompanied by blockade of intrarenal renin upregulation and ANG II accumulation. These data demonstrate an excellent therapeutic potential for doxercalciferol in diabetic renal disease and confirm the concept that blockade of the compensatory renin increase enhances the efficacy of RAS inhibition and produces synergistic therapeutic effects in combination therapy.

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Therapeutic Effect of Sarpogrelate, a New 5-Hydroxytryptamine Receptor 2A Antagonist, on Diabetic Nephropathy and Neuropathy

Nephron ◽

10.1159/000190175 ◽

1997 ◽

Vol 76 (2) ◽

pp. 227-229 ◽

Cited By ~ 11

Author(s):

Eiji Ishimura ◽

Yoshiki Nishizawa ◽

Masanori Emoto ◽

Tetsuo Shoji ◽

Masaaki Inaba ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Therapeutic Effect

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Faculty Opinions recommendation of Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong synergism with AT1 receptor antagonist.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1164962.625818 ◽

2009 ◽

Author(s):

Roberto Zatz

Keyword(s):

Vitamin D ◽

Diabetic Nephropathy ◽

Receptor Antagonist ◽

Therapeutic Effect ◽

At1 Receptor ◽

Vitamin D Analog

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Study of Angiopoietin-2 and vascular endothelial growth factor as markers of diabetic nephropathy onset in Egyptians diabetic patients with non-albuminuric state

Diabetes & Metabolic Syndrome Clinical Research & Reviews ◽

10.1016/j.dsx.2019.03.016 ◽

2019 ◽

Vol 13 (2) ◽

pp. 1623-1627

Author(s):

Mohammad H. Aly ◽

Mohammad A. Arafat ◽

Ola A. Hussein ◽

Hanaa H. Elsaid ◽

Ayman R. Abdel-Hammed

Keyword(s):

Vascular Endothelial Growth Factor ◽

Diabetic Nephropathy ◽

Growth Factor ◽

Diabetic Patients ◽

Vascular Endothelial ◽

Angiopoietin 2 ◽

Endothelial Growth Factor

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Exploring the Mechanisms Underlying the Therapeutic Effect of Salvia Miltiorrhiza Against Diabetic Nephropathy Using Network Pharmacology and Molecular Docking

10.21203/rs.3.rs-85980/v1 ◽

2020 ◽

Author(s):

Li-Li Zhang ◽

Lin Han ◽

Xin-Miao Wang ◽

Yu Wei ◽

Jing-Hui Zheng ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Molecular Docking ◽

Therapeutic Effect ◽

Molecular Mechanisms ◽

Function Analysis ◽

Salvia Miltiorrhiza ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Ppi Network ◽

Active Ingredients

Abstract BackgroundThe mechanisms underlying the therapeutic effect of Salvia Miltiorrhiza (SM) against diabetic nephropathy (DN) using systematic network pharmacology and molecular docking methods were examined.MethodsTCMSP database was used to screen the active ingredients of SM. Gene targets were obtained using Swiss Target Prediction and TCMSP databases. Related targets of DN were retrieved from the Genecards and DisGeNET databases. Next, a PPI network was constructed using the common targets of SM-DN in the STRING database. The Metascape platform was used for GO function analysis and Cytoscape plug-in ClueGO was used for KEGG pathway enrichment analysis. Molecular docking was performed using iGEMDOCK and AutoDock Vina software. Pymol and LigPlos were used for mapping the network. ResultsSixty-six active ingredients and 189 targets were screened from SM. Among them, 64 targets overlapped with DN targets. The PPI network diagram revealed that AKT1, VEGFA, IL6, TNF, MAPK1, TP53, EGFR, STAT3, MAPK14, and JUN were the top 10 relevant targets. GO and KEGG analyses mainly focused on advanced glycation end products, oxidative stress, inflammatory response, and immune regulation. Molecular docking revealed that the potential target genes closely related to DN, including TNF, NOS2, and AKT1, were more stable in combination with salvianolic acid B, and their stability was better than that of tanshinone IIA.ConclusionThis study reveals the active components and potential molecular mechanisms involved in the therapeutic effect of SM against DN and provides a reference for the wide application of SM in clinically managing DN.

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