The kidney proximal tubules are involved in reabsorbing twothirds of the glomerular ultrafiltrate, a key Ca 2؉ -modulated process that is essential for maintaining homeostasis in body fluid compartments. The basolateral membranes of these cells have a Ca 2؉ -ATPase, which is thought to be responsible for the fine regulation of intracellular Ca 2؉ levels. In this paper we show that nanomolar concentrations of ceramide (Cer 50 ؍ 3.5 nM), a natural product derived from sphingomyelinase activity in biological membranes, promotes a 50% increase of Ca Important molecular transport processes take place across the epithelium of kidney proximal tubules. The basolateral membranes (BLM) 4 of kidney proximal tubules cells contain different active transporters, or ion pumps, such as the very abundant Na ϩ K ϩ -ATPase, which is considered to be the molecular machinery responsible for Na ϩ reabsorption (1). Other ion pumps are not so numerous, but some, such as the plasma membrane calcium pump, play important roles in the fine regulation of intracellular ion concentrations. Our group has recently shown that Ca 2ϩ -ATPase is exclusively located and active in caveolin-cholesterol-rich membrane microdomains or lipid rafts in the kidney BLM (2). These membranes have also been shown to house different cell signaling systems that are initiated by the activation of either different lipid kinases, with further generation of bioactive molecules (3, 4), or protein kinases associated with the BLM (5-8).The location of the BLM Ca 2ϩ -ATPase in caveolin-cholesterol-rich domains adds ceramides to the emerging potential regulatory network in these membranes, because those microdomains are also rich in sphingolipids (9). Rafts are thought to be present in the outer leaflet of the cell membrane, where sphingomyelin, the precursor of ceramide (Cer) in a pathway catalyzed by sphingomyelinases, appears to be predominantly located. An important concept is that the assembly of the outer leaflet lipid rafts would alter the inner leaflet, thus enabling the different steps required for signal transduction to be coordinated (for review, see Ref. 10).Many studies during the past decade have shown that smaller lipid rafts are merged into large membrane domains when sphingomyelin is hydrolyzed and Cer is generated (Refs. 11 and 12; see also Ref. 10 for review). The generation of Cer molecules and their self-association leads to dramatic changes in plasma membranes with further formation of small Cer-rich microdomains, which are able to fuse spontaneously to others resulting in large domains called platforms (12)(13)(14). Therefore, Cer-enriched microdomains seem to play an important role in facilitating and amplifying signaling processes, via different types of cell surface receptors, resulting in clusters of receptors and other cell signaling machinery that facilitate the effective transduction of different signals (10).The importance of Cer in different cell processes is not only related to its physicochemical properties. It can be also considered a c...
The basolateral membranes of kidney proximal tubule cells have (Na(+)+K(+))-ATPase and Na(+)-ATPase activities, involved in Na(+) reabsorption. We showed that ceramide (Cer) modulates protein kinase A (PKA) and protein kinase C (PKC), which are involved in regulating ion transporters. Here we show that ceramide, promotes 60% inhibition of Na(+)-ATPase activity (I(50) approximately 100nM). This effect was completely reversed by inhibiting PKA but did not involve the classic PKC signaling pathway. In these membranes we found the Cer-activated atypical PKC zeta (PKCzeta) isoform. When PKCzeta is inhibited, Cer ceases to inhibit the Na(+)-ATPase, allowing the cAMP/PKA signaling pathway to recover its stimulatory effect on the pump. There were no effects on the (Na(+)+K(+))-ATPase. These results reveal Cer as a potent physiological modulator of the Na(+)-ATPase, participating in a regulatory network in kidney cells and counteracting the stimulatory effect of PKA via PKCzeta.
Kidney proximal tubules are a key segment in the reabsorption of solutes and water from the glomerular ultrafiltrate, an essential process for maintaining homeostasis in body fluid compartments. The abundant content of Na+ in the extracellular fluid determines its importance in the regulation of extracellular fluid volume, which is particularly important for different physiological processes including blood pressure control. Basolateral membranes of proximal tubule cells have the classic Na+ + K+-ATPase and the ouabain-insensitive, K+-insensitive, and furosemide-sensitive Na+-ATPase, which participate in the active Na+ reabsorption. Here, we show that nanomolar concentrations of ceramide-1 phosphate (C1P), a bioactive sphingolipid derived in biological membranes from different metabolic pathways, promotes a strong inhibitory effect on the Na+-ATPase activity (C1P50 ≈ 10 nM), leading to a 72% inhibition of the second sodium pump in the basolateral membranes. Ceramide-1-phosphate directly modulates protein kinase A and protein kinase C, which are known to be involved in the modulation of ion transporters including the renal Na+-ATPase. Conversely, we did not observe any effect on the Na+ + K+-ATPase even at a broad C1P concentration range. The significant effect of ceramide-1-phosphate revealed a new potent physiological and pathophysiological modulator for the Na+-ATPase, participating in the regulatory network involving glycero- and sphingolipids present in the basolateral membranes of kidney tubule cells.
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