Neuropathy target esterase catalyzes osmoprotective renal synthesis of glycerophosphocholine in response to high NaCl

Abstract

Glycerophosphocholine (GPC) is an osmoprotective compatible and counteracting organic osmolyte that accumulates in renal inner medullary cells in response to high NaCl and urea. We previously found that high NaCl increases GPC in renal [Madin-Darby canine kidney (MDCK)] cells. The GPC is derived from phosphatidylcholine, catalyzed by a phospholipase that was not identified at that time. Neuropathy target esterase (NTE) was recently shown to be a phospholipase B that catalyzes production of GPC from phosphatidylcholine. The purpose of the present study was to test whether NTE contributes to the high NaCl-induced increase of GPC synthesis in renal cells. We find that in mouse inner medullary collecting duct cells, high NaCl increases NTE mRNA within 8 h and NTE protein within 16 h. Diisopropyl fluorophosphate, which inhibits NTE esterase activity, reduces GPC accumulation, as does an siRNA that specifically reduces NTE protein abundance. The 20-h half-life of NTE mRNA is unaffected by high NaCl. TonEBP͞OREBP is a transcription factor that is activated by high NaCl. Knockdown of TonEBP͞OREBP by a specific siRNA inhibits the high NaCl-induced increase of NTE mRNA. Further, the lower renal inner medullary interstitial NaCl concentration that occurs chronically in ClCK1 ؊/؊ mice and acutely in normal mice given furosemide is associated with lower NTE mRNA and protein. We conclude that high NaCl increases transcription of NTE, likely mediated by TonEBP͞OREBP, and that the resultant increase of NTE expression contributes to increased production and accumulation of GPC in mammalian renal cells in tissue culture and in vivo.diisopropyl fluorophosphate ͉ phospholipase B

A Novel Glycerophosphodiester Phosphodiesterase, GDE5, Controls Skeletal Muscle Development via a Non-enzymatic Mechanism

“…In contrast, an intriguing feature of mammalian GPPDEs is that these enzymes show restricted substrate specificities, strongly suggesting the physiological roles of mammalian GP-PDEs as a determinant for GroPIns or GroPCho levels in mammalian cells. GroPIns has been shown to be involved in the control of cell proliferation, cell chemotaxis, and cell morphology, affecting in the last case actin cytoskeletal rearrangements through the activation of small GTPases of the Rho family (9,34,35), whereas GroPCho is reportedly an osmoprotective compatible and counteracting organic osmolyte that accumulates in renal inner medullary cells in response to high NaCl and urea (8,36,37). A recent study suggests that GDE2 contributes to osmotic regulation as a GroPCho phosphodiesterase (38).…”

Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase

“…SWS mutant flies show spongiform lesions within the CNS, glial hyperwrapping around neurons, and neuronal apoptosis. Recently, it was found that NTE also has an important function in mammalian renal cells (22). High NaCl concentrations in the renal inner medulla induce an increase of glycerophosphocholine (GPC), an organic osmolyte and osmoprotective compatible that is derived from PC.…”

High NaCl- and urea-induced posttranslational modifications that increase glycerophosphocholine by inhibiting GDPD5 phosphodiesterase

“…High NaCl and high urea increase abundance of GPC, but by somewhat different mechanisms. High NaCl increases RNA and protein abundance of NTE, and thus its phospholipase activity, which catalyzes production of GPC from phosphatidylcholine, but high urea does not (4). Also, high NaCl decreases mRNA abundance of GDPD5 via an increase of its degradation rate, although high urea does not.…”

“…GPC, like other compatible organic osmolytes (2), protects cells by stabilizing intracellular macromolecules against the perturbing effects of the high NaCl and urea (3). GPC is synthesized from phosphatidylcholine, catalyzed by phospholipase B activity of neuropathy target esterase (NTE) (4,5), and it is degraded to choline and glycerol-3-phosphate, catalyzed by glycerophosphocholine-phosphodiesterase (GPC-PDE) activity of the phosphodiesterase phosphodiesterase domain containing 5 (GDPD5) (6,7). High NaCl and high urea increase abundance of GPC, but by somewhat different mechanisms.…”