Therapeutic Effect of Amaranthus hybridus on Diabetic Nephropathy

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.

Download Full-text

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

Download Full-text

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

Download Full-text

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.

Download Full-text

Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00430.2012 ◽

2013 ◽

Vol 304 (1) ◽

pp. E87-E99 ◽

Cited By ~ 39

Author(s):

Wenpeng Cui ◽

Bing Li ◽

Yang Bai ◽

Xiao Miao ◽

Qiang Chen ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Therapeutic Effect ◽

Mechanistic Study ◽

Therapeutic Effects ◽

Related Factor ◽

Diabetic Mice ◽

Proteasomal Activity ◽

Nrf2 Activation ◽

Renal Tubular

Oxidative stress is a major cause of diabetic nephropathy. Upregulation of the key antioxidative transcription factor, nuclear factor-erythroid 2-related factor 2 (Nrf2), was found to prevent the development of diabetic nephropathy. The present study was designed to explore the therapeutic effect of Nrf2 induced by proteasomal inhibitor MG132 at a low dose (10 μg/kg) on diabetic nephropathy. Transgenic type 1 diabetic (OVE26) mice displayed renal dysfunction with albuminuria by 3 mo of age, at which time MG132 treatment was started. After 3-mo treatment with MG132, renal function, morphology, and biochemical changes were examined with real-time PCR, Western blotting, and immunohistochemical examination. Compared with age-matched, nontreated diabetic mice, MG132-treated diabetic mice showed significant improvements in terms of renal structural and functional alterations. These therapeutic effects were associated with increased Nrf2 expression and transcriptional upregulation of Nrf2-regulated antioxidants. Mechanistic study using human renal tubular HK11 cells confirmed the role of Nrf2, as silencing the Nrf2 gene with its specific siRNA abolished MG132 prevention of high-glucose-induced profibrotic response. Furthermore, diabetes was found to significantly increase proteasomal activity in the kidney, an effect that was significantly attenuated by 3 mo of treatment with MG132. These results suggest that MG132 upregulates Nrf2 function via inhibition of diabetes-increased proteasomal activity, which can provide the basis for the therapeutic effect of MG132 on the kidney against diabetes-induced oxidative damage, inflammation, fibrosis, and eventual dysfunction.

Download Full-text