Inhibition of ceramide–redox signaling pathway blocks glomerular injury in hyperhomocysteinemic rats

Abstract

Ceramide-activated NAD(P)H oxidase has been reported to participate in homocysteine (Hcys)-induced abnormal metabolism of the extracellular matrix (ECM) in rat glomerular mesangial cells. However, it remains unknown whether this ceramide-redox signaling pathway contributes to glomerular injury induced by hyperhomocysteinemia (hHcys) in vivo. The present study was designed to address this question, defining the role of ceramide and activated NAD(P)H oxidase in the development of hHcys-induced glomerular injury. Uninephrectomized Sprague-Dawley rats were fed a folate-free diet for 8 weeks to produce hHcys and the de novo ceramide synthesis inhibitor myriocin or the NAD(P)H oxidase inhibitor apocynin was administrated. Rats with folate-free diet significantly increased plasma Hcys levels, renal ceramide levels, and NAD(P)H oxidase activity accompanied by marked glomerular injury. Treatment of rats with myriocin significantly reduced ceramide levels and improved glomerular injury, as shown by decreased urinary albumin excretion and reduced glomerular damage index. ECM components changed towards to normal levels with decreased tissue inhibitor of metalloproteinase-1 and increased matrix metalloproteinase-1 activity. NAD(P)H oxidase activity and Rac GTPase activity were reduced by 69 and 66%, respectively. In rats treated with apocynin, similar beneficial effects in protecting glomeruli from hHcys-induced injury were observed. These results support the view that de novo ceramide production is involved in Hcys-induced NAD(P)H oxidase activity in the kidney of hHcys rats and indicate the important role of ceramide-mediated redox signaling in hHcys-induced glomerular injury in rats.

Ceramide: A common pathway for atherosclerosis?

“…It was a direct consequence of stimulation of ceramide synthase. In a more recent study, Yi et al also showed that blocking the de novo synthesis of ceramide with myriocin significantly reduced homocysteine-induced ceramide production and glomerular injury in rats [47]. These studies demonstrate that the detrimental effects of homocysteine on many organ systems are mediated by ceramide signaling.…”

Coronary Endothelial Dysfunction Induced by Nucleotide Oligomerization Domain-Like Receptor Protein with Pyrin Domain Containing 3 Inflammasome Activation During Hypercholesterolemia: Beyond Inflammation

“…We further explored the molecular mechanisms mediating the production of these novel effects of Nlrp3 inflammasome in ECs. The production of ROS was shown to be one of the major early factors mediating death factor-induced endothelial injury (5,6,40,49,50). NADPH oxidase-derived ROS associated with ceramide-enriched membrane raft clustering (21,47,52) were found to primarily contribute to the death factor or adipokine visfatin-mediated endothelial dysfunction (13,17,46,48,52,53).…”

Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure

“…High Hcy has been reported to produce a sustained and abnormal elevation of glomerular arterial wall stress through generation of ROS (57,58). This stress initiates a complex and progressive glomerular remodeling, including activation of MMPs, collagen degradation, glomerular hypertrophy, and dysfunction (22,37).…”