The inositol Inpp5k 5-phosphatase affects osmoregulation through the vasopressin-aquaporin 2 pathway in the collecting system

Abstract

Inositol Inpp5k (or Pps, SKIP) is a member of the inositol polyphosphate 5-phosphatases family with a poorly characterized function in vivo. In this study, we explored the function of this inositol 5-phosphatase in mice and cells overexpressing the 42-kDa mouse Inpp5k protein. Inpp5k transgenic mice present defects in water metabolism characterized by a reduced plasma osmolality at baseline, a delayed urinary water excretion following a water load, and an increased acute response to vasopressin. These defects are associated with the expression of the Inpp5k transgene in renal collecting ducts and with alterations in the arginine vasopressin/aquaporin-2 signalling pathway in this tubular segment. Analysis in a mouse collecting duct mCCD cell line revealed that Inpp5k overexpression leads to increased expression of the arginine vasopressin receptor type 2 and increased cAMP response to arginine vasopressin, providing a basis for increased aquaporin-2 expression and plasma membrane localization with increased osmotically induced water transport. Altogether, our results indicate that Inpp5k 5-phosphatase is important for the control of the arginine vasopressin/aquaporin-2 signalling pathway and water transport in kidney collecting ducts. [13,17, 29, 40]. It also regulates the activity of many ion channels and transporters [35,36]. PtdIns(4,5)P2 is mainly localized in the inner leaflet of plasma membranes, but smaller pools have been detected in intracellular membranes, including Golgi, endoplasmic reticulum, endosomes and lamellipodia [13]. Mechanistically, a very large number of proteins are recruited to PtdIns(4,5)P2 via pleckstrin homology (PH), phagocyte oxidase (PX), Fab1p, YOTB, Vac1p and EEA1 (FYVE), epsin N-terminal homology (ENTH) domains or through small patches of basic amino acids [13,18, 28]. PtdIns(4,5,)P2 also serves as precursor of five essential signalling molecules: diacylglycerol, inositol (1,4,5)-trisphosphate, PtdIns4P, PtdIns5P and PtdIns(3,4,5)P3 [13,17]. In non stimulated cells, PtdIns(3,4,5)P3 levels are very low in the plasma membrane, reaching ~0.1% of the level of PtdIns(4,5)P2 [13,17]. Upon cell activation, PtdIns(3,4,5)P3 levels are transiently increased by a factor ranging from 2-to 100-fold. This phosphoinositide is implicated in the control of cell survival, growth and proliferation, resistance to apoptosis, regulation of cytoskeleton dynamics, membrane trafficking, cell migration, and many of the metabolic responses to insulin [12,13].PtdIns(3,4,5)P3 regulates a wide variety of effector proteins primarily by binding and recruiting specific proteins.In mammalian cells, PtdIns(4,5)P2 and/or PtdIns(3,4,5)P3 are substrates for several members of the phosphoinositide 5-phosphatases family, including Inppl1 (or

The duplication 17p13.3 phenotype: Analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes

“…Neither is a compelling autism candidate gene based on their known functions. Overexpression of Inpp5k in mice affects osmoregulation in kidney collecting ducts [Pernot et al, ]. Heterozygous missense mutations in the motor domain of MYO1C cause hearing loss in humans [Adamek et al, ].…”

Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases

“…Skip + / − mice exhibit increased insulin sensitivity, glucose uptake and reduced weight gain on a high-fat diet [77]. Transgenic overexpression of SKIP leads to defective kidney function: abnormal osmoregulation and decreased water excretion [112].…”

Severe acute dehydration in a desert rodent elicits a transcriptional response that effectively prevents kidney injury

“…The transcriptomic mechanisms used by P. eremicus to regulate water appear to depend on INPP5K ( Fig. 4; inositol polyphosphate-5-phosphatase K), which is known to be expressed in the collecting duct, is functionally responsible for urine concentration (75), and is involved in insulin signaling (10). Interestingly, this gene may also have a role in negative regulation of actin in the extracellular matrix (4), which provides yet another indication of the general depression of turnover in the extracellular matrix, as does the lower expression of fibronectin and the collagens.…”