TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity

Binzhi Zhang, Ganesan Ramesh, Satoshi Uematsu, Shizuo Akira, W. Brian Reeves

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(-/-)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(-/-) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(-/-) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-α and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.

Original languageEnglish (US)
Pages (from-to)923-932
Number of pages10
JournalJournal of the American Society of Nephrology
Volume19
Issue number5
DOIs
StatePublished - May 1 2008

Fingerprint

Cisplatin
Inflammation
Kidney
Wounds and Injuries
Acute Kidney Injury
Toll-Like Receptors
Leukocytes
Cytokines
Adaptive Immunity
p38 Mitogen-Activated Protein Kinases
Innate Immunity
Bone Marrow
Epithelial Cells
Urine
Serum

ASJC Scopus subject areas

  • Nephrology

Cite this

TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. / Zhang, Binzhi; Ramesh, Ganesan; Uematsu, Satoshi; Akira, Shizuo; Reeves, W. Brian.

In: Journal of the American Society of Nephrology, Vol. 19, No. 5, 01.05.2008, p. 923-932.

Research output: Contribution to journalArticle

Zhang, Binzhi ; Ramesh, Ganesan ; Uematsu, Satoshi ; Akira, Shizuo ; Reeves, W. Brian. / TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. In: Journal of the American Society of Nephrology. 2008 ; Vol. 19, No. 5. pp. 923-932.
@article{716878e2ba7e4b9999517317b3bb78d9,
title = "TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity",
abstract = "The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(-/-)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(-/-) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(-/-) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-α and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.",
author = "Binzhi Zhang and Ganesan Ramesh and Satoshi Uematsu and Shizuo Akira and Reeves, {W. Brian}",
year = "2008",
month = "5",
day = "1",
doi = "10.1681/ASN.2007090982",
language = "English (US)",
volume = "19",
pages = "923--932",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "5",

}

TY - JOUR

T1 - TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity

AU - Zhang, Binzhi

AU - Ramesh, Ganesan

AU - Uematsu, Satoshi

AU - Akira, Shizuo

AU - Reeves, W. Brian

PY - 2008/5/1

Y1 - 2008/5/1

N2 - The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(-/-)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(-/-) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(-/-) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-α and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.

AB - The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(-/-)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(-/-) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(-/-) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-α and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.

UR - http://www.scopus.com/inward/record.url?scp=44049103058&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44049103058&partnerID=8YFLogxK

U2 - 10.1681/ASN.2007090982

DO - 10.1681/ASN.2007090982

M3 - Article

C2 - 18256356

AN - SCOPUS:44049103058

VL - 19

SP - 923

EP - 932

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 5

ER -