Increasing evidence suggests that apoptosis of tubular cells and renal inflammation
mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was
to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in
endotoxin (lipopolysaccharide, LSP)-induced AKI. A sepsis model was established by intraperitoneal
injection of a single non-lethal LPS dose after short-term simvastatin pretreatment. The severity of
the inflammatory injury was expressed as renal damage scores (RDS). Apoptosis of tubular cells was
detected by Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL assay)
(apoptotic DNA fragmentation, expressed as an apoptotic index, AI) and immunohistochemical
staining for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL and survivin. We found
that endotoxin induced severe renal inflammatory injury (RDS = 3.58 ± 0.50), whereas simvastatin
dose-dependently prevented structural changes induced by LPS. Furthermore, simvastatin 40 mg/kg
most profoundly attenuated tubular apoptosis, determined as a decrease of cytochrome C, caspase-3
expression, and AIs (p < 0.01 vs. LPS). Conversely, simvastatin induced a significant increase of
Bcl-XL and survivin, both in the strong inverse correlations with cleaved caspase-3 and cytochrome
C. Our study indicates that simvastatin has cytoprotective effects against LPS-induced tubular
apoptosis, seemingly mediated by upregulation of cell-survival molecules, such as Bcl-XL and
survivin, and inhibition of the mitochondrial cytochrome C and downstream caspase-3 activation.
