1. FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats.
- Author
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Sanajou D, Ghorbani Haghjo A, Argani H, Roshangar L, Ahmad SNS, Jigheh ZA, Aslani S, Panah F, Rashedi J, and Mesgari Abbasi M
- Subjects
- Administration, Oral, Angiotensin II Type 1 Receptor Blockers administration & dosage, Angiotensin II Type 1 Receptor Blockers therapeutic use, Animals, Benzamides administration & dosage, Biomarkers blood, Biomarkers metabolism, Biomarkers urine, Diabetic Nephropathies metabolism, Diabetic Nephropathies pathology, Diabetic Nephropathies physiopathology, Drug Therapy, Combination, Glomerular Filtration Barrier metabolism, Glomerular Filtration Barrier pathology, Glomerular Filtration Barrier physiopathology, Injections, Intraperitoneal, Macrophages drug effects, Macrophages immunology, Macrophages pathology, Male, Microscopy, Fluorescence, Phosphorylation drug effects, Podocytes drug effects, Podocytes immunology, Podocytes metabolism, Podocytes pathology, Protein Processing, Post-Translational drug effects, Random Allocation, Rats, Wistar, Receptor for Advanced Glycation End Products metabolism, Renal Insufficiency complications, Renal Insufficiency metabolism, Renal Insufficiency physiopathology, Transcription Factor RelA metabolism, Valsartan administration & dosage, Benzamides therapeutic use, Diabetes Mellitus, Experimental complications, Diabetic Nephropathies prevention & control, Glomerular Filtration Barrier drug effects, Receptor for Advanced Glycation End Products antagonists & inhibitors, Renal Insufficiency prevention & control, Valsartan therapeutic use
- Abstract
Despite the effectiveness of renin-angiotensin blockade in retarding diabetic nephropathy progression, a considerable number of patients still develop end-stage renal disease. The present investigation aims to evaluate the protective potential of FPS-ZM1, a selective inhibitor of receptor for advanced glycation end products (RAGE), alone and in combination with valsartan, an angiotensin receptor blocker, against glomerular injury parameters in streptozotocin-induced diabetic rats. FPS-ZM1 at 1 mg/kg (i.p.), valsartan at 100 mg/kg (p.o.), and their combination were administered for 4 weeks, starting 2 months after diabetes induction in rats. Tests for kidney function, glomerular filtration barrier, and podocyte slit diaphragm integrities were performed. Combined FPS-ZM1/valsartan attenuated diabetes-induced elevations in renal levels of RAGE and phosphorylated NF-κB p65 subunit. It ameliorated glomerular injury due to diabetes by increasing glomerular nephrin and synaptopodin expressions, mitigating renal integrin-linked kinase (ILK) levels, and lowering urinary albumin, collagen type IV, and podocin excretions. FPS-ZM1 also improved renal function as demonstrated by decreasing levels of serum cystatin C. Additionally, the combination also alleviated indices of renal inflammation as revealed by decreased renal monocyte chemoattractant protein 1 (MCP-1) and chemokine (C-X-C motif) ligand 12 (CXCL12) expressions, F4/80-positive macrophages, glomerular TUNEL-positive cells, and urinary alpha-1-acid glycoprotein (AGP) levels. These findings underline the benefits of FPS-ZM1 added to valsartan in alleviating renal glomerular injury evoked by diabetes in streptozotocin rats and suggest FPS-ZM1 as a new potential adjunct to the conventional renin-angiotensin blockade.
- Published
- 2018
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