Hydrogen sulfide-producing cystathionine γ-lyase is critical in the progression of kidney fibrosis

• Published in: Free radical biology & medicine 2017-11, Vol.112, p.423-432
• Main Authors: Han, Sang Jun, Noh, Mi Ra, Jung, Jung-Min, Ishii, Isao, Yoo, Jeongsoo, Kim, Jee In, Park, Kwon Moo
• Format: Article
• Language: English
• Subjects: Actins - genetics; Actins - metabolism; Animals; Chronic kidney disease; Cystathionine beta-Synthase - genetics; Cystathionine beta-Synthase - metabolism; Cystathionine gamma-Lyase - deficiency; Cystathionine gamma-Lyase - genetics; Cystathionine γ-lyase; Disease Progression; Epithelial Cells - enzymology; Epithelial Cells - pathology; Female; Fibrosis; Gene Expression Regulation; Glutathione - biosynthesis; Hydrogen sulfide; Hydrogen Sulfide - metabolism; Kidney - enzymology; Kidney - pathology; Kidney fibrosis; Kidney Tubules - enzymology; Kidney Tubules - pathology; Mice; Mice, Knockout; Mitochondria - metabolism; Mitochondria - pathology; Oxidation-Reduction; Reactive oxygen species; Renal Insufficiency, Chronic - enzymology; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - pathology; Signal Transduction; Sulfurtransferases - genetics; Sulfurtransferases - metabolism; Superoxides - metabolism; Ureteral Obstruction - enzymology; Ureteral Obstruction - genetics; Ureteral Obstruction - pathology
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2017.08.017

Cystathionine γ-lyase (CSE), the last key enzyme of the transsulfuration pathway, is involved in the production of hydrogen sulfide (H2S) and glutathione (GSH), which regulate redox balance and act as important antioxidant molecules. Impairment of the H2S- and GSH-mediated antioxidant system is associated with the progression of chronic kidney disease (CKD), characterized by kidney fibrosis and dysfunction. Here, we evaluated the role of CSE in the progression of kidney fibrosis after unilateral ureteral obstruction (UUO) using mice deficient in the Cse gene. UUO of wild-type mice reduced the expression of H2S-producing enzymes, CSE, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase in the obstructed kidneys, resulting in decreased H2S and GSH levels. Cse gene deletion lowered H2S and GSH levels in the kidneys. Deleting the Cse gene exacerbated the decrease in H2S and GSH levels and increase in superoxide formation and oxidative damage to proteins, lipids, and DNA in the kidneys after UUO, which were accompanied by greater kidney fibrosis, deposition of extracellular matrixes, expression of α-smooth muscle actin, tubular damage, and infiltration of inflammatory cells. Furthermore, Cse gene deletion exacerbated mitochondrial fragmentation and apoptosis of renal tubule cells after UUO. The data provided herein constitute in vivo evidence that Cse deficiency impairs renal the H2S- and GSH-producing activity and exacerbates UUO-induced kidney fibrosis. These data propose a novel therapeutic approach against CKD by regulating CSE and the transsulfuration pathway. [Display omitted] •Ureteral obstruction (UO) impairs H2S-producing enzymes, CSE, CBS, and 3-MST.•UO reduces levels of H2S and GSH in the kidney.•CSE deletion reduces H2S and GSH and exacerbates UO-induced those in the kidney.•CSE deletion worsens oxidative injury and apoptosis, resulting in fibrosis.