Role of phosphatidylinositol 3-kinase in oxidative stress-induced disruption of tight junctions. Vol. 278 (2003) 49239-49245

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

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Novel Role of Phosphatidylinositol 3-Kinase in CD28-mediated Costimulation

Journal of Biological Chemistry ◽

10.1074/jbc.m005051200 ◽

2000 ◽

Vol 276 (12) ◽

pp. 9003-9008 ◽

Cited By ~ 40

Author(s):

Yohsuke Harada ◽

Eri Tanabe ◽

Ryosuke Watanabe ◽

Bonnie D. Weiss ◽

Akira Matsumoto ◽

...

Keyword(s):

Phosphatidylinositol 3 Kinase ◽

Phosphatidylinositol 3

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Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)41901-6 ◽

1994 ◽

Vol 269 (5) ◽

pp. 3568-3573 ◽

Cited By ~ 10

Author(s):

T. Okada ◽

Y. Kawano ◽

T. Sakakibara ◽

O. Hazeki ◽

M. Ui

Keyword(s):

Glucose Transport ◽

Essential Role ◽

Selective Inhibitor ◽

Phosphatidylinositol 3 Kinase ◽

Rat Adipocytes ◽

Phosphatidylinositol 3

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cAMP-stimulated Na+ transport in H441 distal lung epithelial cells: role of PKA, phosphatidylinositol 3-kinase, and sgk1

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00340.2003 ◽

2004 ◽

Vol 287 (4) ◽

pp. L843-L851 ◽

Cited By ~ 33

Author(s):

Christie P. Thomas ◽

Jason R. Campbell ◽

Patrick J. Wright ◽

Russell F. Husted

Keyword(s):

Apical Cell ◽

P38 Map Kinase ◽

Lung Epithelial Cells ◽

Epithelial Cell Line ◽

Phosphatidylinositol 3 Kinase ◽

Transport Pathway ◽

Early Effect ◽

Sustained Effect ◽

Phosphatidylinositol 3

H441 cells, a bronchiolar epithelial cell line, develop a cAMP-regulated benzamil-sensitive Na+ transport pathway on permeable supports (Itani OA, Auerbach SD, Husted RF, Volk KA, Ageloff S, Knepper MA, Stokes JB, Thomas CP. Am J Physiol Lung Cell Mol Physiol 282: L631–L641, 2002). To understand the molecular basis for the stimulation of Na+ transport, we delineated the role of specific intracellular pathways and examined the effect of cAMP on αβγ-epithelial Na+ channel (ENaC) and sgk1 expression. Na+ transport increases within 5 min of cAMP stimulation and is sustained for >24 h. The sustained effect of cAMP on Na+ transport is abolished by LY-294002, an inhibitor of phosphatidylinositol 3-kinase, by H89, an inhibitor of PKA, or by SB-202190, an inhibitor of p38 MAP kinase. The sustained effect of cAMP was associated with increases in α-ENaC mRNA and protein but without a detectable increase in βγ-ENaC and sgk1. The early effect of cAMP on Na+ transport is brefeldin sensitive and is mediated via PKA. These results are consistent with a model where the early effect of cAMP is to increase trafficking of Na+ channels to the apical cell surface whereas the sustained effect requires the synthesis of α-ENaC.

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PI(4,5)P2 controls slit diaphragm formation and endocytosis in Drosophila nephrocytes

10.1101/2021.06.22.449474 ◽

2021 ◽

Author(s):

Max Gass ◽

Sarah Borkowsky ◽

Marie-Luise Lotz ◽

Rita Schroeter ◽

Pavel Nedvetsky ◽

...

Keyword(s):

Plasma Membrane ◽

Model System ◽

Dominant Negative ◽

Slit Diaphragm ◽

Phosphatidylinositol 3 Kinase ◽

Ectopic Activation ◽

Phosphatidylinositol 4 ◽

Asymmetrically Distributed ◽

Phosphatidylinositol 3

Drosophila nephrocytes are an emerging model system for mammalian podocytes and podocyte-associated diseases. Like podocytes, nephrocytes exhibit characteristics of epithelial cells, but the role of phospholipids in polarization of these cells is yet unclear. In epithelia phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) and phosphatidylinositol(3,4,5)-trisphosphate (PI(3,4,5)P3) are asymmetrically distributed in the plasma membrane and determine apical-basal polarity. Here we demonstrate that both phospholipids are present in the plasma membrane of nephrocytes, but only PI(4,5)P2 accumulates at slit diaphragms. Knockdown of Skittles, a phosphatidylinositol(4)phosphate 5-kinase, which produces PI(4,5)P2, abolished slit diaphragm formation and led to strongly reduced endocytosis. Notably, reduction in PI(3,4,5)P3 by overexpression of PTEN or expression of a dominant-negative phosphatidylinositol-3-Kinase did not affect nephrocyte function, whereas enhanced formation of PI(3,4,5)P3 by constitutively active phosphatidylinositol-3-Kinase resulted in strong slit diaphragm and endocytosis defects by ectopic activation of the Akt/mTOR pathway. Thus, PI(4,5)P2 but not PI(3,4,5)P3 is essential for slit diaphragm formation and nephrocyte function. However, PI(3,4,5)P3 has to be tightly controlled to ensure nephrocyte development.

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The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival

Journal of General Virology ◽

10.1099/vir.0.19771-0 ◽

2004 ◽

Vol 85 (5) ◽

pp. 1065-1076 ◽

Cited By ~ 158

Author(s):

S. Cooray

Keyword(s):

Signal Transduction ◽

Pivotal Role ◽

Phosphatidylinositol 3 Kinase ◽

Virus Survival ◽

Phosphatidylinositol 3

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Phosphatidylinositol 3-Kinase and Prostaglandylinositol Cyclic Phosphate (Cyclic PIP), a Mediator of Insulin Action, in the Signal Transduction of Insulin

Biological Chemistry ◽

10.1515/bc.2000.140 ◽

2000 ◽

Vol 381 (11) ◽

pp. 1139-1141 ◽

Cited By ~ 1

Author(s):

A. Gypakis ◽

H.K. Wasner

Keyword(s):

Insulin Receptor ◽

Glucose Transport ◽

Functional Role ◽

Specific Inhibitor ◽

Insulin Receptor Substrate ◽

Phosphatidylinositol 3 Kinase ◽

Downstream Signaling ◽

Cyclic Phosphate ◽

Phosphatidylinositol 3

Abstract It has been suggested that downstream signaling from the insulin receptor to the level of the protein kinases and protein phosphatases is accomplished by prostaglandylinositol cyclic phosphate (cyclic PIP), a proposed second messenger of insulin. However, evidence points also to both phosphatidylinositol 3-kinase, which binds to the tyrosine phosphorylated insulin receptor substrate-1, and the Ras complex in insulin's downstream signaling. We have examined whether a correlation exists between these various observations. It was found that wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, prevented insulin-induced, as well as cyclic PIP-induced activation of glucose transport, indicating that PI 3-kinase action on glucose transport involves downstream signaling of both insulin and cyclic PIP. Wortmannin has no effect on cyclic PIP synthase activity nor on the substrate production for cyclic PIP synthesis either, indicating that the functional role of PI 3-kinase is exclusively downstream of cyclic PIP.

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