Influenza virus inhibits amiloride-sensitive Na<sup>+</sup>channels in respiratory epithelia

Kunzelmann, Karl; Beesley, Alex H.; King, Nicholas J. C.; Karupiah, Gunasegaran; Young, J. A.; Cook, David I.

doi:10.1073/pnas.160041997

Cited by 108 publications

(138 citation statements)

References 43 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Infection with H5N1, compared with seasonal H1N1, influenza virus also led to greater down-regulation of the Na,K-ATPase and CFTR transporter proteins in alveolar epithelium. Influenza virus infection was previously shown to impair alveolar fluid transport by inhibiting epithelial sodium channel activity through interaction of viral hemagglutinin (15) and matrix (16) proteins with the epithelial sodium channel. To our knowledge, ours is the first demonstration of impaired alveolar fluid clearance and protein permeability due to soluble mediators released by infected alveolar epithelium.…”

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Chan

Kuok

Leung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

182

181

View full text Add to dashboard Cite

Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.

show abstract

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Chan

Kuok

Leung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

182

181

View full text Add to dashboard Cite

show abstract

“…It has also been recently shown that ENaC activity is down-regulated after influenza virus infection of mouse tracheal epithelia, contributing to the accumulation of edema fluid in the airway (Kunzelmann et al 2000;Matthay et al 2002). This down-regulation is dependent on viral hemagglutinin binding to a cell surface receptor, which was shown to activate phospholipase C and protein kinase C (PKC).…”

Section: Discussionmentioning

confidence: 99%

Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript

Dunn¹,

Ishigami²,

Pankow

et al. 2002

J Hum Genet

View full text Add to dashboard Cite

reported counterpart. Variant 13-A precludes the formation of a transcript encoding a full-length Ca 2ϩ -dependent lipid-binding (C2) domain with very high evolutionary conservation among NEDD4L orthologs. A similar C2 domain in the paralogous NEDD4 gene plays a significant role in the transfer of its product to the apical membrane of epithelial cells. Differential function of NEDD4L isoforms could prove significant in blood pressure regulation through an effect on ENaC-dependent sodium reabsorption.

show abstract

“…Apical and basolateral surfaces of the monolayer were simultaneously perfused with a solution containing (in mM) 130 NaCl, 1 CaCl 2 , 1 KCl, 1 MgCl 2 , 5 glucose, 10 HEPES, pH 7.4, maintained at 37°C. Experiments were carried out under open circuit conditions (24). Transepithelial resistance was measured by applying short (1 s) repetitive 10-A current pulses across the epithelium.…”

Section: Methodsmentioning

confidence: 99%

Akt Mediates the Effect of Insulin on Epithelial Sodium Channels by Inhibiting Nedd4-2

Lee

Dinudom

Sánchez-Pérez

et al. 2007

Journal of Biological Chemistry

132

141

View full text Add to dashboard Cite

The epithelial sodium channel (ENaC) plays an important role in transepithelial Na ؉ absorption; hence its function is essential for maintaining Na ؉ and fluid homeostasis and regulating blood pressure. Insulin is one of the hormones that regulates activity of ENaC. In this study, we investigated the contribution of two related protein kinases, Akt (also known as protein kinase B) and the serum-and glucocorticoid-dependent kinase (Sgk), on insulin-induced ENaC activity in Fisher rat thyroid cells expressing ENaC. Overexpression of Akt1 or Sgk1 significantly increased ENaC activity, whereas expression of a dominant-negative construct of Akt1, Akt1 K179M , decreased basal activity of ENaC. Inhibition of the endogenous expression of Akt1 and Sgk1 by short interfering RNA not only inhibited ENaC but also disrupted the stimulatory effect on ENaC of insulin and of the downstream effectors of insulin, phosphatidylinositol 3-kinase and PDK1. Conversely, overexpression of Akt1 or Sgk1 increased expression of ENaC at the cell membrane and overcame the inhibitory effect of Nedd4-2 on ENaC. Furthermore, mutation of consensus phosphorylation sites on Nedd4-2 for Akt1 and Sgk1, Ser 342 and Ser 428 , completely abolished the inhibitory effect of Sgk1 and Akt1 on Nedd4-2 action. Together these data suggest that both Akt and Sgk are components of an insulin signaling pathway that increases Na ؉ absorption by upregulating membrane expression of ENaC via a regulatory system that involves inhibition of Nedd4-2.Transepithelial Na ϩ absorption across the kidney distal collecting duct, the distal colon, and the ducts of the exocrine glands occurs via the epithelial sodium channels (ENaC) 4 and is tightly regulated by hormones such as aldosterone, insulin, and arginine vasopressin. These hormones play an important role in Na ϩ and fluid homeostasis, and their activities are critical in the regulation of blood pressure. Comprehensive knowledge of the signal transduction pathways that underlie the effect of these hormones on ENaC is therefore essential for our understanding of the development of homeostatic abnormalities such as essential hypertension.Insulin is a peptide hormone that manifests a stimulatory effect on Na ϩ transport in a variety of epithelia (1-5). The immediate natriferic effect of insulin is attributed to an increase in the open probability of ENaC (5, 6) or an increase in the number of active ENaC at the apical membrane (4, 7). Acting through insulin receptor substrate-1, insulin activates phosphatidylinositol 3-kinase (PI3K), a heterodimeric enzyme that catalyzes the formation of phosphatidylinositol 3,4,5-trisphosphate. This activation is essential for mediating several insulin responses, and PI3K has been identified as integral for mediating the effect of insulin on ENaC (8). For instance, insulin treatment increases colocalization of PI3K with ENaC, thereby promoting translocation of ENaC to the apical membrane (4), whereas inhibition of PI3K by LY294002 prevents insulin-induced translocation of the channel (4) an...

show abstract

Influenza virus inhibits amiloride-sensitive Na⁺channels in respiratory epithelia

Cited by 108 publications

References 43 publications

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript

Akt Mediates the Effect of Insulin on Epithelial Sodium Channels by Inhibiting Nedd4-2

Contact Info

Product

Resources

About

Influenza virus inhibits amiloride-sensitive Na+channels in respiratory epithelia

Cited by 108 publications

References 43 publications

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript

Akt Mediates the Effect of Insulin on Epithelial Sodium Channels by Inhibiting Nedd4-2

Contact Info

Product

Resources

About

Influenza virus inhibits amiloride-sensitive Na⁺channels in respiratory epithelia