PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice

Ahrabi, Ali K.; Terryn, Sara; Valenti, Giovanna; Caron, Nathalie; Gal, Claudine Serradeil–Le; Raufaste, Danielle; Nielsen, Søren; Horie, Shigeo; Verbavatz, Jean‐Marc; Devuyst, Olivier

doi:10.1681/asn.2006010052

Cited by 64 publications

(53 citation statements)

References 55 publications

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“…Although abnormalities have been reported in Pkd1-and Pkd2-haploinsufficient models, 26,27 the understanding and effects of this condition are still limited. On the basis of the biologic properties of PC1, we reasoned that this condition might lead to increased susceptibility to IR.…”

Section: Discussionmentioning

confidence: 99%

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Bastos

Piontek

Silva

et al. 2009

Journal of the American Society of Nephrology

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Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10-to 12-wk-old male noncystic Pkd1 ϩ/Ϫ and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.

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Section: Discussionmentioning

confidence: 99%

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Bastos

Piontek

Silva

et al. 2009

Journal of the American Society of Nephrology

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“…This lack of polycystin proteins has been linked to abnormal cell proliferation, apoptosis, and fluid/ion secretion, all of which contribute to cyst expansion (6,(15)(16)(17)(18)(19)(20). Polycystin-deficient cells have significant abnormalities in basal Ca 2ϩ levels, a situation that could contribute to all of the phenotypes of ADPKD (21)(22)(23). It therefore seems clear that insufficient polycystin expression can result in deregulation of intracellular Ca 2ϩ homeostasis.…”

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confidence: 99%

Polycystin-1 Interacts with Inositol 1,4,5-Trisphosphate Receptor to Modulate Intracellular Ca2+ Signaling with Implications for Polycystic Kidney Disease

Santoso

et al. 2009

Journal of Biological Chemistry

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“…Changes in target gene mRNA levels were determined in duplicate by relative RT-qPCR with a CFX96 TM Real-Time PCR Detection System (Bio-Rad Laboratories, Hercules, CA) using iQ TM SYBR Green Supermix (Bio-Rad) detection of single PCR product accumulation. The PCR conditions, the negative controls, the preparation of the standard curves and the calculation of the reaction efficiencies were as previously described [1].…”

Section: Methodsmentioning

confidence: 99%

“…Water handling at baseline and during various protocols was assessed in individual metabolic cages, after appropriate training, as described [1,5]. Plasma samples and 24-h urine collections were obtained at baseline, and urinary concentrating ability was tested after 24-h water deprivation.…”

Section: Methodsmentioning

confidence: 99%

“…Running title: Inpp5k and the control of renal water transport Eileen Pernot 1,2,7 , Sara Terryn 4,7 , Siew Chiat Cheong Inositol Phosphatase, and Pps, for Putative Phosphatase) [2,7,30,32,33]. These enzymes tightly control the level of the above-mentioned phosphoinositides in a tissue-, cellular-, subcellular-and signalling cascade-specific way.…”

Section: The Inositol Inpp5k 5-phosphatase Affects Osmoregulation Thrmentioning

confidence: 99%

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

Pernot

Terryn

Cheong

et al. 2011

Pflugers Arch - Eur J Physiol

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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

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PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice

Abstract: Mutations in

Cited by 64 publications

References 55 publications

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Polycystin-1 Interacts with Inositol 1,4,5-Trisphosphate Receptor to Modulate Intracellular Ca2+ Signaling with Implications for Polycystic Kidney Disease

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

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