The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo

Abstract

Podocyte injury, a major contributor to the pathogenesis of diabetic nephropathy, is caused at least in part by the excessive generation of reactive oxygen species (ROS). Overproduction of superoxide by the NADPH oxidase isoform Nox4 plays an important role in podocyte injury. The plant extract silymarin is attributed antioxidant and antiproteinuric effects in humans and in animal models of diabetic nephropathy. We investigated the effect of silybin, the active constituent of silymarin, in cultures of mouse podocytes and in the OVE26 mouse, a model of type 1 diabetes mellitus and diabetic nephropathy. Exposure of podocytes to high glucose (HG) increased 60% the intracellular superoxide production, 90% the NADPH oxidase activity, 100% the Nox4 expression, and 150% the number of apoptotic cells, effects that were completely blocked by 10 μM silybin. These in vitro observations were confirmed by similar in vivo findings. The kidney cortex of vehicle-treated control OVE26 mice displayed greater Nox4 expression and twice as much superoxide production than cortex of silybin-treated mice. The glomeruli of control OVE26 mice displayed 35% podocyte drop out that was not present in the silybin-treated mice. Finally, the OVE26 mice experienced 54% more pronounced albuminuria than the silybin-treated animals. In conclusion, this study demonstrates a protective effect of silybin against HG-induced podocyte injury and extends this finding to an animal model of diabetic nephropathy.

Adenosine kinase inhibition protects the kidney against streptozotocin-induced diabetes through anti-inflammatory and anti-oxidant mechanisms

“…Reactive oxygen species (ROS) are considered a causal link between elevated glucose levels and the development of diabetic renal injury [54,55]. ABT702 inhibited oxidative and nitrosative stress in diabetic retina as it decreased superoxide and nitrotyrosine levels [25].…”

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

“…30,31 Furthermore, because podocytes express AT1Rs, AngII may induce Nox5 expression and activity in human podocytes. 32 As determined by quantitative RT-PCR, Nox5 mRNA expression was significantly increased in response to AngII at both 2 and 8 hours ( Figure 1E).…”

Effects of palmitoylethanolamide and silymarin combination treatment in an animal model of kidney ischemia and reperfusion

“…Furthermore, its antioxidant, anti-inflammatory, and anticarcinogenic properties were demonstrated in the studies conducted with silymarin against oxidative stress, inflammatory responses, and benzoil peroxide-induced tumor promotion in mice (Katiyar, 2005). With regard to kidney damage, silymarin has been studied in vitro in different experimental models relevant fo renal pathology, including human glomerular mesangial cells stimulated by inflammatory mediators (Chang et al, 2006) and, using purified silibinin, conditionally immortalized mouse podocytes studied in vitro in the presence of high glucose levels (Khazim et al, 2013). In both cases a protective effect was observed, although the exact mechanism could not be determined.…”

“…In both cases a protective effect was observed, although the exact mechanism could not be determined. Silymarin has been studied in several experimental rodent models, including administration of nephrotoxic compounds (Satyanarayana et al, 2001), renal ischemia/reperfusion (Turgut et al, 2008) and diabetes (Khazim et al, 2013). Clinical efficacy has been observed in CKD patients with different stages of the disease, including those undergoing hemodialysis (Fallahzadeh et al, 2012;Meyers and Briggs, 2012).…”