Ischemia-reperfusion reduces cystathionine-β-synthase-mediated hydrogen sulfide generation in the kidney

Abstract

Cystathionine-β-synthase (CBS) catalyzes the rate-limiting step in the transsulfuration pathway for the metabolism of homocysteine (Hcy) in the kidney. Our recent study demonstrates that ischemia-reperfusion reduces the activity of CBS leading to Hcy accumulation in the kidney, which in turn contributes to renal injury. CBS is also capable of catalyzing the reaction of cysteine with Hcy to produce hydrogen sulfide (H2S), a gaseous molecule that plays an important role in many physiological and pathological processes. The aim of the present study was to examine the effect of ischemia-reperfusion on CBS-mediated H2S production in the kidney and to determine whether changes in the endogenous H2S generation had any impact on renal ischemia-reperfusion injury. The left kidney of Sprague-Dawley rat was subjected to 45-min ischemia followed by 6-h reperfusion. The ischemia-reperfusion caused lipid peroxidation and cell death in the kidney. The CBS-mediated H2S production was decreased, leading to a significant reduction in the renal H2S level. The activity of cystathionine-γ-lyase, another enzyme responsible for endogenous H2S generation, was not significantly altered in the kidney upon ischemia-reperfusion. Partial restoration of CBS activity by intraperitoneal injection of the nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide not only increased renal H2S levels but also alleviated ischemia-reperfusion-induced lipid peroxidation and reduced cell damage in the kidney tissue. Furthermore, administration of an exogenous H2S donor, NaHS (100 μg/kg), improved renal function. Taken together, these results suggest that maintenance of tissue H2S level may offer a renal protective effect against ischemia-reperfusion injury.

Impact of endogenous hydrogen sulfide on toll-like receptor pathway in renal ischemia/reperfusion injury in rats

“…[13][14][15][16][17] In a rat renal IRI model, H 2 S level was significantly decreased; however, administration of the exogenous H 2 S donor, NaHS, ameliorated IRI and improved renal function. 18 Similar observation has been obtained in living mice. 19 In a bilateral renal IR model using Wistar rats, administration of CSE inhibitor PAG impaired recovery of renal function with increased serum creatinine and urea after 45-min ischemia and 72-h reperfusion.…”

Vitamin D Up-regulates Glucose Transporter 4 (GLUT4) Translocation and Glucose Utilization Mediated by Cystathionine-γ-lyase (CSE) Activation and H2S Formation in 3T3L1 Adipocytes

“…Determination of CSE Activity-Intracellular CSE activity was determined following the method of Xu et al (14) using an enzyme-coupled assay with lactate dehydrogenase. Using pyridoxal phosphate as a coenzyme, CSE first catalyzes the ␣,␥-elimination of cystathionine to give cysteine, which is then converted into pyruvate, ammonia, and H 2 S by the action of the same enzyme (CSE).…”

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).…”

“…CBS and CSE activities were determined according to the methods described previously (6,47). 120 ll of homogenate was mixed with 20 ll of 10 mM L-cysteine, 20 ll of 10 mM DLhomocysteine, 20 ll of 0.05 mM S-adenosylmethionine, and 20 ll of 2mM pyridoxal 5 ¢ -phosphate and incubated for 90 min at 37°C.…”