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Eur J Pharmacol. 2018 Oct 26;842:40-48. doi: 10.1016/j.ejphar.2018.10.035. [Epub ahead of print]

Reduction of renal tubular injury with a RAGE inhibitor FPS-ZM1, valsartan and their combination in streptozotocin-induced diabetes in the rat.

Author information

1
Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
2
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: ghorbani@tbzmed.ac.ir.
3
Urology and Nephrology Research Center, Beheshti University of Medical Sciences, Tehran, Iran.
4
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
5
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
6
Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
7
Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.
8
Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

Abstract

Receptor for advanced glycation end-products (RAGE) is involved in the pathogenesis of diabetic nephropathy. FPS-ZM1, a selective RAGE inhibitor, in combination with valsartan were investigated for their protective potentials on the renal markers of tubular injury in streptozotocin-induced diabetic rats. Rats were assigned into groups of receiving FPS-ZM1 (1 mg/kg/day), valsartan (100 mg/kg/day), and FPS-ZM1 plus valsartan (1 mg/kg/day and 100 mg/kg/day, respectively) for one month. Kidney histology, renal inflammation and oxidative stress, and renal and urinary markers of tubular injury were investigated. FPS-ZM1 and valsartan in combination more significantly attenuated renal expressions of tumor necrosis factor-alpha and interleukin-6 genes and reduced urinary levels of interleukin-6. Moreover, the combination elevated renal NAD+/NADH ratios and Sirt1 activities, and mitigated nuclear acetylated NF-κB p65 levels. In addition to alleviating indices of oxidative stress i.e. malondialdehyde, superoxide dismutase and glutathione peroxidase, the combination of FPS-ZM1 and valsartan more effectively upregulated the renal levels of master antioxidant proteins Nrf2, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase-1. Additionally, this dual therapy ameliorated more efficiently the indices of renal tubular injuries as indicated by decreased renal kidney injury molecule-1 levels as well as reduced urinary levels of cystatin C, retinol binding protein, and beta-2-microglobulin. While FPS-ZM1 alone had no appreciable effects on the renal fibrosis, the combination treatment ameliorated fibrosis better than valsartan in the kidneys. Collectively, these findings underline the extra benefits of FPS-ZM1 and valsartan dual administrations in obviating the renal tubular cell injury in streptozotocin-induced diabetic rats partly by suppressing renal inflammation and oxidative stress.

KEYWORDS:

Advanced glycation end-products; Diabetic rats; FPS-ZM1; Inflammation; Oxidative stress; Tubular injury

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