L-carnitine treatment attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction

Abstract

Background/Aims: Accumulating evidence indicates that L-carnitine (LC) protects against multiorgan damage through its antioxidant properties and preservation of the mitochondria. Little information is available about the effects of LC on renal fibrosis. This study examined whether LC treatment would provide renoprotection in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Methods: Sprague-Dawley rats that underwent UUO were treated daily with LC for 7 or 14 days. The influence of LC on renal injury caused by UUO was evaluated by histopathology, and analysis of gene expression, oxidative stress, mitochondrial function, programmed cell death, and phosphatidylinositol 3-kinase (PI3K)/ AKT/forkhead box protein O 1a (FoxO1a) signaling. In addition, H 2 O 2 -exposed human kidney cells (HK-2) were treated with LC. Results: LC treatment inhibited expression of proinflammatory and profibrotic cytokines, and was followed by a significant attenuation of tubulointerstitial inflammation and fibrosis. The increased oxidative stress caused by UUO was associated with mitochondrial dysfunction and excessive apoptosis and autophagy via PI3K/AKT/FoxO1a-dependent signaling, and this was abrogated by administration of LC. In H 2 O 2 -exposed HK-2 cells, LC decreased intracellular production of reactive oxygen species, and suppressed expression of profibrotic cytokines and reduced the number of apoptotic cells. Conclusions: LC protects against the progression of tubulointerstitial fibrosis in an obstructed kidney.

Effect of L-carnitine on potassium dichromate-induced nephrotoxicity in rats: modulation of PI3K/AKT signaling pathway

“…Zhao et al . stated that L-carnitine use was accompanied by amelioration of renal inflammation-induced via unilateral ureteral obstruction through inhibition of pro-inflammatory cytokines and attenuation of tubulointerstitial inflammation in rats ( 39 ). Moreover, L-carnitine; in one study; was able to improve renal function and mitigate histological abnormalities in rats suffering from chronic kidney disease ( 40 ).…”

Inhibition of RIP1-RIP3-mediated necroptosis attenuates renal fibrosis via Wnt3α/β-catenin/GSK-3β signaling in unilateral ureteral obstruction

“…This concept is supported by studies that used antioxidant drugs or genetic knockout of cyclooxygenase-2 [ 18 ]. In addition, we and others have reported a relation between mitochondria and oxidative stress because mitochondria play canonical roles in cellular respiration and oxidative phosphorylation, and are a major source of ROS [ 19 ]. The finding herein that RIP inhibitors or ICG-001 can regulate the expression of oxidant and antioxidant enzymes, decrease ROS production, and balance mitochondria-controlling genes suggests that they may be able to protect mitochondrial morphological integrity.…”

Screening and identification of key microRNAs and regulatory pathways associated with the renal fibrosis process

“…87 The metabolic transition of renal fibroblasts from oxidative phosphorylation to aerobic glycolysis (Warburg effect) activates fibroblasts, whereas the inhibition of aerobic glycolysis in renal fibroblasts can significantly reduce RF. 88 KEGG pathway analysis showed that the pathways enriched among the target genes of the DE-miRNAs, including the ErbB, VEGF and TNF signalling pathways, are related to cardiomyocyte fibrosis and renal fibrosis, diabetic nephropathy and chronic renal failure, 89,90 along with apoptosis, glycerophospholipid metabolism, pyrimidine metabolism, tryptophan metabolism and glutamate metabolism, 91–94 all of which are related to renal interstitial fibrosis. GO enrichment analysis of the DE-miRNA target genes further showed that these genes are significantly associated with metabolic processes.…”