Inhibition of cystathionine-β-synthase activity during renal ischemia-reperfusion: role of pH and nitric oxide

Abstract

Our recent study (Prathapasinghe GA, Siow YL, O K. Am J Physiol Renal Physiol 292: F1354-F1363, 2007) indicates that homocysteine (Hcy) plays a detrimental role in ischemia-reperfusion-induced renal injury. Elevation of renal Hcy concentration during ischemia-reperfusion is attributed to reduced activity of cystathionine-beta-synthase (CBS) that catalyzes the rate-limiting step in the transsulfuration pathway for the metabolism of the majority of Hcy in the kidney. However, the mechanisms of impaired CBS activity in the kidney are unknown. The aim of this study was to investigate the effects of pH and nitric oxide (NO) on the CBS activity in the kidney during ischemia-reperfusion. The left kidney of a Sprague-Dawley rat was subjected to ischemia-reperfusion. The CBS activity was significantly reduced in kidneys subjected to ischemia alone (15-60 min) or subjected to ischemia followed by reperfusion for 1-24 h. The pH was markedly reduced in kidneys upon ischemia. Injection of alkaline solution into the kidney partially restored the CBS activity during ischemia. Further analysis revealed that reduction of CBS activity during reperfusion was accompanied by an elevation of NO metabolites (nitrate and nitrite) in the kidney tissue. Injection of a NO scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), restored the CBS activity in the kidneys subjected to ischemia-reperfusion. Treatment with PTIO could abolish ischemia-reperfusion-induced lipid peroxidation and prevent cell death in the kidney. These results suggested that metabolic acidosis during ischemia and accumulation of NO metabolites during reperfusion contributed, in part, to reduced CBS activity leading to an elevation of renal Hcy levels, which in turn, played a detrimental role in the kidney.

Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

“…The same disorder explained decreased biosynthesis of downstream products of transsulfuration (GSx, hTa, and Tau). CBS activity depends on the cellular redox state and is inhibited by NO or acidosis [46] and activated by ROS [45]. The balance between NO and ROS levels was shown as an important mechanism of the response to paclitaxel at low concentration [13,46].…”

Protective Role of Methionine Sulfoxide Reductase a Against Ischemia/Reperfusion Injury in Mouse Kidney and Its Involvement in the Regulation of Transsulfuration Pathway

“…Recent evidence from human and animal studies has demonstrated that H 2 S is directly involved in various diseases, including hypertension, atherosclerosis, and end-stage renal disease (42). The cytoprotective effects of H 2 S have been reported in a variety of organs, including the heart, brain, liver, and kidney, against I/R injury (5,37,47). In this study, we determined that the deletion of MsrA induced a reduction in the levels of plasma H 2 S and accelerated the post-I/R decrease of H 2 S in plasma and kidney tissue.…”

“…Wu et al reported that renal I/R inhibits CBS gene expression mediated by a transcription factor Sp1, leading to the accumulation of homocysteine and the reduction of H 2 S in the rat kidney (46). Previous studies reported that I/R reduces CBS and CSE activities and H 2 S production, leading to increased kidney damage and oxidative stress (37,47). In the heart, Calvert et al reported that CSE gene-transfer and exogenous H 2 S treatment protected the heart against I/R injury by attenuating oxidative stress (5).…”

Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor‐Erythroid 2‐Related Factor 2 (Nrf2)‐Dependent Signaling in Chronic Heart Failure

“…The interrelation of NO‐H 2 S and their biochemical interactions are complex and currently unclear. While some studies have shown that NO‐H 2 S positively affect each other's production and function,35, 51 other studies report contrarian, if not directly opposite findings 55, 56. Studies have shown that H 2 S has opposing effects on NOS/NO metabolism.…”