Up-regulation of glyoxalase 1 by mangiferin prevents diabetic nephropathy progression in streptozotocin-induced diabetic rats

Abstract

Advanced glycation endproducts (AGEs) and its precursor methylglyoxal are associated with diabetic nephropathy (DN). Mangiferin has many beneficial biological activities, including anti-inflammatory, anti-oxidative and anti-diabetic effects. We investigated the effect of mangiferin on DN and its potential mechanism associated with glyoxalase 1 (Glo-1), a detoxifying enzyme of methylglyoxal, in streptozotocin-induced rat model of DN. Diabetic rats were treated orally with mangiferin (15, 30, and 60 mg/kg) or distilled water for 9 weeks. Kidney tissues were collected for morphologic observation and the determination of associated biochemical parameters. The cultured mesangial cells were used to measure the activity of Glo-1 in vitro. Chronic treatment with mangiferin significantly ameliorated renal dysfunction in diabetic rats, as evidenced by decreases in albuminuria, blood urea nitrogen, kidney weight index, periodic acid-schiff stain positive mesangial matrix area, glomerular extracellular matrix expansion and accumulation, and glomerular basement membrane thickness. Meanwhile, mangiferin treatment caused substantial increases in the enzymatic activity of Glo-1 in vivo and in vitro, and protein and mRNA expression of Glo-1, reduced levels of AGEs and the protein and mRNA expression of their receptor (RAGE) in the renal cortex of diabetic rats. Moreover, mangiferin significantly attenuated oxidative stress damage as reflected by the lowered malondialdehyde and the increased glutathione levels in the kidney of diabetic rats. However, mangiferin did not affect the blood glucose and body weight of diabetic rats. Therefore, mangiferin can remarkably ameliorate DN in rats through inhibiting the AGEs/RAGE aix and oxidative stress damage, and Glo-1 may be a target for mangiferin action.

Introduction

As a global disease, diabetes nephropathy (DN) is one of the most severe diabetic microangiopathies and accounts for approximately one third of end-stage renal disease (Rossing, 2006). Several mechanisms have been considered to be involved in the pathogenesis of DN and other diabetes-associated complications, such as the accumulation of advanced glycation endproducts (AGEs), and oxidative stress (Brownlee, 2001). AGEs are a major mediator of the untoward effects of hyperglycemia (Suzuki and Miyata, 1999). AGEs may generate from nonenzymatic reactions between proteins and carbonyl compounds, like methylglyoxal (MG), glyoxal, and 3-deoxyglucosone (Brownlee et al., 1988). Protein glycation caused by MG, a key precursor of AGEs formation, may be a central player in the complications of diabetes due to its ability to increase both inflammation and oxidative stress (Di Loreto et al., 2008, Rabbani and Thornalley, 2008, Sena et al., 2012, Yamawaki et al., 2008). MG can accumulate in body and accelerates the formation of AGEs. DN may be related to the accumulation of toxic alpha-oxoaldehydes such as MG. Therefore, therapeutic strategies aimed at reducing dicarbonyl compounds or enhancing their clearance and subsequently inhibiting AGEs formation would be effective to prevent the pathogenesis of DN.

The glyoxalase system is a major detoxication system for dicarbonyl compounds in human body, where glyoxalase 1 (Glo-1) is the rate-limiting enzyme. With reduced glutathione (GSH) as a cofactor, Glo-1 can promptly clear alpha-carbonyl aldehydes, e.g. MG, inhibiting AGEs formation. Glo-1 can also directly inhibit AGEs formation in bovine endothelial cells (Shinohara et al., 1998) and GM7373 endothelial cells (Thornalley, 2003). Moreover, Glo-1 over-expression has been shown to reduce indices of diabetic complications (Brouwers et al., 2011, Queisser et al., 2010). Hyperglycemia-induced reactive oxygen species have increased the expression of AGEs and RAGE (receptor for AGEs), which is mediated by MG, which can be normalized by Glo-1 over-expression (Brouwers et al., 2011, Yao and Brownlee, 2010). Glo-1 can attenuate damages in mitochondria from oxidative stress (Rabbani and Thornalley, 2008). Moreover, Glo-1 over-expression can reduce oxidative stress damage in diabetic rats (Brouwers et al., 2011). Thus, Glo-1 may become a preventative and therapeutic target of diabetic complications, including DN.

Mangiferin, also called chinonin, is a major glucoside of xanthone in Rhizome Anemarrhena. Mangiferin has many biological activities, including anti-inflammatory, anti-oxidative and anti-diabetic effects (Miura et al., 2001, Muruganandan et al., 2005, Prabhu et al., 2006). Mangiferin improves diabetic complications in heart and kidney (Li et al., 2010, Muruganandan et al., 2002). Several studies have showed that this compound inhibits AGEs formation and aldose reductase activity in in vitro study (Tang et al., 2004, Yoshikawa et al., 2001). Li et al. (2010) illustrate that mangifrein could prevent the progression of DN by suppressing renal fibrosis. All these reports indicate that mangiferin may have a beneficial effect on the progression of DN. However, the intimate mechanism of mangiferin on DN progression remains unknown. Therefore, our study is aimed to investigate the effects of mangiferin on the nephropathy in streptozotocin-induced diabetic rats, a rodent model of type 1 diabetes, and the pathological factors related to Glo-1 in diabetic condition.