FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced
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ORIGINAL ARTICLE
FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats Davoud Sanajou 1,2 & Amir Ghorbani Haghjo 3 & Hassan Argani 4 & Leila Roshangar 5 & Saeed Nazari Soltan Ahmad 1 & Zahra Ashrafi Jigheh 1 & Somayeh Aslani 1 & Fatemeh Panah 1 & Jalil Rashedi 1 & Mehran Mesgari Abbasi 6 Received: 16 March 2018 / Accepted: 1 June 2018 # University of Navarra 2018
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. Keywords Diabetic nephropathy . FPS-ZM1 . Podocyte injury . STZ-induced diabetic rats . Valsartan
Introduction * Amir Ghorbani Haghjo [email protected] 1
Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
2
Student Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3
Biotechnology Research Center, Tabriz University of Medical Sciences, Golgasht Avenue, P.O. Box 14711, Tabriz 5166614711, Iran
4
Urology and Nephrology Research Center, Beheshti University of Medical Sciences, Tehran, Iran
5
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
6
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Diabetic nephropathy (DN), developing in 20 to 40% of both type 1 and type 2 dia
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