Differential Renoprotective Actions of Simvastatin and Rosuvastatin in Streptozotocin-Induced Diabetes in Sprague-Dawley Rat

Abstract

Diabetic nephropathy (DN) is the most frequent cause of the end-stage renal disease (ESRD) in about 33% of diabetic patients. The present study aimed to explore the renoprotective effects of simvastatin (SV) and rosuvastatin (RSU) on the kidney of streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rat model. As a result of induction of diabetes, serum [cystatin C, transforming growth factor-beta (TGF-β), and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] and tissue [interleukin 1 beta (IL-1β), interleukin 10 (IL-10), prostaglandin E2 (PGE2), cytochrome c, malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), GSH/GSSG ratio) markers showed significant increase than negative controls except tissue total glutathione (tGSH). Both SV and RSU significantly shifted the levels back toward near non-diabetic values. Both exerted the same renoprotective effect indicated by a significant decrease in cystatin C. However, SV significantly lowered IL-10, GSH/GSSG ratio, MDA, and 8-OHdG than RSU. Similarly, RSU significantly lowered cytochrome c and GSSG than SV. In conclusion, SV and RSU have differential renoprotective effects via alteration of growth factor, inflammatory, oxidative stress, DNA damage, and apoptotic signaling pathways.

Statins and the Diabetic Kidney

“…In experimentally streptozotocin-induced diabetes in a rat model disturbances in the levels of inflammatory markers were observed. The mean level of IL-1β, was several times that of normal controls [23,24]. These high IL-1β levels were significantly attenuated, approximately, to the same levels, by treatment with either simvastatin or rosuvastatin suggesting their protective potential against diabetesinduced renal injury.…”

“…It was suggested that IL-1β preferentially stimulates the production of prostaglandins and many of its biological activities are probably due to such increase in PGE2 production [27]. The decrease of IL-1β level, following treatment with simvastatin and rosuvastatin, was accompanied by a similar fall in PGE2 levels with no significant difference between the two drugs [23]. Similarly, pretreatment with either of the two drugs was able to significantly reduce lipopolysaccharide (LPS)-induced PGE2 production in microglial-like cells [25].…”

“…An increase in the local production of renal prostaglandins (PGs) has been observed in clinical and experimental diabetic nephropathy and PG synthesis is augmented in the glomeruli of streptozotocin-induced diabetic rats [23,24,30]. The overproduction of PGE2 plays an important role in the end organ damage in diabetes [31].…”

“…Reduced TGF-β signaling activity has been shown to be associated with improved renal outcomes in experimental animal studies [33]. Serum TGF-β levels, in STZ-induced diabetic rats, were significantly increased compared with normal control rats [23]. Transforming growth factor-β signaling pathway has been shown to play a critical role in regulation of the extracellular matrix (ECM) accumulation of the kidney to promote the renal glomerulosclerosis [34] and inflammation in diabetic rat model [35].…”

“…Its levels and signaling are enhanced in renal cells during the progression of diabetic nephropathy [36]. The effective decrease, of serum TGF-β by both simvastatin and rosuvastatin is indicative of their potential antifibrotic and hence renoprotective effects [23]. This may be a pointer for possible attenuation of the progression of kidney damage.…”