Abstract
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.
Highlights
The main nephron segment referred to Na+ reabsorption, and with C1P potentially available and/or recruited to this niche, here, we explore the action of C1P in different kinases that are known to modulate Na+ + K+-ATPase and the ouabain-insensitive, K+-insensitive, and furosemide-sensitive Na+-ATPase, studying the regulation of these Na+ transporters in the basolateral membranes (BLM) by C1P and unrevealing the cell signaling cascades involved
The results presented here in combination with previous results from our group clearly show that Cer [33] and C1P modulated the BLM associated Protein Kinase A (PKA) and Protein Kinase C (PKC), which appeared to mediate the effects elicited by ceramides on Na+-ATPase
From the results presented here, a signaling cascade starting with Cer production and further phosphorylation to C1P is an efficient pathway for inhibiting Na+-ATPase in renal proximal tubules cells through BLM associated PKA and PKC as effectors [17]
Summary
From the initial studies in the 90s, bioactive sphingolipids have emerged as an important class of cell signaling molecules, which are rapidly mobilized upon cell stimulation and are able to trigger different cell signaling cascades that culminate with specific cell responses [1,2]. The ability of Cer and C1P in triggering different protein kinases, and the increasing list of effectors shown to be modulated by these sphingolipids [2,12,31,32] allowed us to hypothesize that both bioactive sphingolipids could be responsible for the regulation of Na+ transporters in the BLM This could be interesting due to the capacity of ceramides triggering effector proteins, as already demonstrated by our group [18,33], and due to the importance of Cer for the assembly of membrane rafts and caveolae as well as large membrane microdomains, so called platforms, which are specific regions in plasma membranes where signaling molecules and effectors are co-localized [8,9,34,35]. From the results presented here, these described pathways involved in the regulatory network responsible for Na+ reabsorption may provide some means for the development of widespread new therapeutic strategies for different renal diseases and more complex pathologies such as hypertension
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