Altered sphingomyelinase and ceramide expression in the setting of ischemic and nephrotoxic acute renal failure

Abstract

Diverse physical and chemical stimuli can activate sphingomyelinases (SMases), resulting in sphingomyelin (SM) hydrolysis with ceramide release. Since ceramide can profoundly impact a host of homeostatic mechanisms, the concept of a "SM (or SMase) signaling pathway" has emerged. We recently documented that ceramide levels fall abruptly during renal ischemia, and then rebound to twice normal values during early reperfusion (30 to 90 min) Therefore, the present study assessed whether these ceramide changes are paralleled, and hence potentially mediated, by comparable changes in SMase activity. Mice were subjected to 45 minutes of renal ischemia +/- 30 minutes, 90 minutes, or 24 hours of reperfusion. Renal cortices (or isolated proximal tubules) were then assayed for SMase activity (acidic, neutral forms). To characterize whether early post-ischemic ceramide increments are a relatively persistent event, ceramide was assayed following a 24-hour reperfusion period. Finally, to assess whether the observed perturbations were unique to post-ischemic injury, SMase and ceramide were quantified in the setting of glycerol-induced myohemoglobinuria and anti-glomerular basement membrane (alpha GBM) antibody-induced acute renal failure (ARF). Ischemia induced abrupt declines (approximately 50%) in both acidic and neutral SMase activities, and these persisted in an unremitting fashion throughout 24 hours of reperfusion. Nevertheless, increased ceramide expression (2x normal) resulted. Myohemoglobinuria also suppressed acidic/neutral SMases, and again, "paradoxical" ceramide increments were observed. Finally, alpha GBM nephritis increased ceramide levels, but in this instance, a correlate was increased SMase activity. These results suggest that: (1) ceramide is an acute renal "stress rectant" increasing in response to diverse renal insults; (2) this response may occur independently of the classic SM pathway, since the ceramide increments can seemingly be dissociated from increased SMase activity; and (3) given the well documented impact of ceramide and the SM(ase) pathway on apoptosis, cell proliferation, differentiation, and tissue inflammation, the present results have potentially broad ranging implications for the induction and evolution of diverse forms of ARF.

Mn‐SOD antisense upregulates in vivo apoptosis of squamous cell carcinoma cells by anticancer drugs and γ‐rays regulating expression of the BCL‐2 family proteins, COX‐2 and p21

“…29,30 In contrast, oxidative stress by radiation, anticancer agents and postischemic reperfusions induces cell impairment and apoptosis through peroxidation of proteins and DNA and activation of the molecules in the death-signaling pathways. [31][32][33] Although the details of ROI-associated apoptotic signaling have not been clarified, the finding that ROIs reduce ⌬⌿ m and finally activate caspase-9 and caspase-3 is well known. [13][14][15]27 In addition, ROIs activate kinases associated with apoptosis.…”

Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation

“…It was shown that hypoxia to PC12 cells results in enhanced ceramide generation through the activation of neutral sphingomyelinase (37). In contrast, other studies have shown that in ischemic injury to kidneys or cultured kidney cells the activity of sphingomyelinases is decreased rather than increased (39). Currently, there is no information on the role of ceramide synthase in the regulation of ceramide in hypoxia-reoxygenation injury.…”

“…Although the role of ceramide has been studied in apoptotic cell death in response to a variety of stimuli, there is limited information of a role of ceramide in hypoxia-reoxygenation injury. In vivo studies of ischemic injury to the kidney (39,40) or brain (19) as well as in vitro study of hypoxic injury to cultured PC12 cells (37) have shown an increase in ceramide level. However, the cause-effect relationship between an alteration of ceramide and cytotoxicity is not known in hypoxiareoxygenation injury to renal tubular epithelial cells, and the pathways for ceramide generation in ischemia-reperfusion or hypoxia-reoxygenation injury remain to be elucidated.…”

Cadmium-induced ceramide formation triggers calpain-dependent apoptosis in cultured kidney proximal tubule cells

“…Despite the fact that a few studies in cultured PT cells have implicated ceramides as an "acute renal stress reactant" that increases in response to diverse ischemic or toxic insults (4,28,70), until now there have been no studies investigating the role of ceramides in Cd 2ϩ -induced PT cell death. Here we report for the first time that exposure to 10 -50 M Cd 2ϩ for 3-6 h induces an increased formation of cellular ceramides, which trigger apoptosis of cultured rat kidney PT cells via a calpaindependent pathway.…”