Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells’ Survival and Hindering Cytochrome C-Mediated Apoptosis

Abstract

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.

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

“…Excessive ROS can stimulate p53 that induces apoptosis. Moreover, B-cell lymphoma-2-associated X (Bax) is activated by ROS and/or p53 and translocated to the outer membrane of the mitochondria, leading to the leakage of cytochrome c (cyto c), which is a strong inducer of apoptosis ( 49 ). Therefore, the apoptosis signaling pathway is closely related to sepsis-AKI, and inhibiting apoptosis may be an effective strategy for the prevention and treatment of sepsis-AKI.…”

ATRvD1 Attenuates Renal Tubulointerstitial Injury Induced by Albumin Overload in Sepsis-Surviving Mice

“…The contribution of TNF-α to renal damage was confirmed using TNFR1 −/− in endotoxemia, which prevents inflammation and apoptosis [51]. In addition, the in-creased expression of casp-3 cleavage has been detected in endotoxin-and CLP-induced AKI [52,53], along with higher renal IL-1β levels in cisplatin-associated AKI [54]. It is known that IL-1β activates nuclear factor kappa B pathway, playing an important role in the transcription of pro-inflammatory cytokines.…”

Kidney Inflammation, Injury and Regeneration 2020

“…In this current Special Edition, thirteen original research articles are presented: twelve in vivo studies in a murine or rat model and one in vitro study [ 3 ]. Seven studies show results from AKI models [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ], five from fibrosis models (or CKD models) [ 9 , 11 , 12 , 13 , 14 ] and two from a transplant rejection model [ 4 , 15 ] (two studies used two different in vivo models).…”

“…The study revealed a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis [ 7 ]. The findings of Nežić and coworkers investigated the molecular mechanism involved in the reno-protective effects of simvastatin in an endotoxin-induced AKI model [ 5 ]. The study indicated that simvastatin, a well-known lipid-lowering medication, has cytoprotective effects on induced tubular apoptosis, mediated by the upregulation of cell survival molecules and inhibition of the mitochondrial proteins.…”

“…The study indicated that simvastatin, a well-known lipid-lowering medication, has cytoprotective effects on induced tubular apoptosis, mediated by the upregulation of cell survival molecules and inhibition of the mitochondrial proteins. Therefore, the authors hypothesized that simvastatin has significant cell-protective effects in septic AKI [ 5 ].…”