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

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.

Gender Differences in the Progression of Experimental Chronic Kidney Disease Induced by Chronic Nitric Oxide Inhibition.

Chronic kidney disease (CKD) is considered a public health problem, assuming epidemic proportions worldwide. In this context, the preponderance of CKD prevalence in male over age-matched female patients is of note. In the present study, we investigated the impact of the gender on the development of experimental CKD induced by chronic nitric oxide (NO) inhibition in Wistar male and female rats through the administration of L-NAME. CKD model induced by L-NAME is characterized by systemic vasoconstriction, resulting in severe hypertension, albuminuria, renal ischemia, glomerulosclerosis, interstitial expansion, and macrophage infiltration. After 30 days of CKD induction, male NAME rats exhibited remarkable albuminuria, augmented cortical histological damage, interstitial inflammation, and fibrosis. Age-matched female NAME rats showed significantly lower albuminuria, diminished glomerular ischemia, and glomerulosclerosis, as well as a significant reduction in the expression of α-smooth muscle actin renal interstitial Ang II+ cells. Thus, the present study demonstrated that female rats submitted to the NAME model developed less severe CKD than males. Female renoprotection could be promoted by both the estrogen anti-inflammatory activity and/or by the lack of testosterone, related to renin-angiotensin-aldosterone system hyperactivation and fibrogenesis. However, the influence of sex hormones on the progression of CKD needs to be further investigated.