Abstract
Diabetic nephropathy (DN) is a progressive kidney disease that is caused by injury to kidney glomeruli. Podocytes are glomerular epithelial cells and play critical roles in the glomerular filtration barrier. Recent studies have shown the importance of regulating the podocyte actin cytoskeleton in early DN. The phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, simultaneously regulates Rac1 and Cdc42, which destabilize the podocyte actin cytoskeleton during early DN. In this study, in order to evaluate the reno-protective effects of wortmannin in early DN by regulating Rac1 and Cdc42, streptozotocin (STZ)-induced proteinuric renal disease (SPRD) rats were treated with wortmannin. The albuminuria value of the SPRD group was 3.55 ± 0.56 mg/day, whereas wortmannin group was 1.77 ± 0.48 mg/day. Also, the albumin to creatinine ratio (ACR) value of the SPRD group was 53.08 ± 10.82 mg/g, whereas wortmannin group was 20.27 ± 6.41 mg/g. Changes in the expression level of nephrin, podocin and Rac1/Cdc42, which is related to actin cytoskeleton in podocytes, by wortmannin administration were confirmed by Western blotting. The expression levels of nephrin (79.66 ± 0.02), podocin (87.81 ± 0.03) and Rac1/Cdc42 (86.12 ± 0.02) in the wortmannin group were higher than the expression levels of nephrin (55.32 ± 0.03), podocin (53.40 ± 0.06) and Rac1/Cdc42 (54.05 ± 0.04) in the SPRD group. In addition, expression and localization of nephrin, podocin and desmin were confirmed by immunofluorescence. In summary, we found for the first time that wortmannin has a reno-protective effect on SPRD rats during the early DN. The beneficial effects of wortmannin in SPRD rats indicate that this compound could be used to delay the progression of the disease during the early DN stage.
Highlights
Diabetic nephropathy (DN) is a major complication caused by the development of diabetes mellitus, which damages the kidneys (Guilbert, 2006)
After 8 weeks of treatment with wortmannin, the albuminuria value (1.77 ± 0.48 mg/dl) in the wortmannin group was decreased when compared with the STZ-induced proteinuric renal disease (SPRD) group (3.55 ± 0.56 mg/dl) (Figure 2A)
Based on the albuminuria and albumin to creatinine ratio (ACR) results, we demonstrated that wortmannin treatment can lower the albuminuria and ACR when compared with the SPRD group
Summary
Diabetic nephropathy (DN) is a major complication caused by the development of diabetes mellitus, which damages the kidneys (Guilbert, 2006). It has been defined as increased protein excretion in urine (Mundel and Reiser, 2010). The glomerulus is injured by glomerular hypertrophy, which is the thickening of the GBM, and the formation of ECM during early DN. These effects lead to glomerular hyperfiltration, hypertension, microalbuminuria and foot process effacement (Jefferson et al, 2008)
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