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Article: Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy

TitleToll-like receptor 4 promotes tubular inflammation in diabetic nephropathy
Authors
Issue Date2012
PublisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.org
Citation
Journal Of The American Society Of Nephrology, 2012, v. 23 n. 1, p. 86-102 How to Cite?
AbstractInflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease fromother causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time- and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IβB/NF-βB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IβB/NF-βB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucose-treated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-βB activation, tubular CCL-2 expression, and interstitialmacrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathwaymay promote tubulointerstitial inflammation in diabetic nephropathy. Copyright © 2012 by the American Society of Nephrology.
Persistent Identifierhttp://hdl.handle.net/10722/148677
ISSN
2015 Impact Factor: 8.491
2015 SCImago Journal Rankings: 4.699
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong KongHKU 7764/07M
Funding Information:

This study was supported by the General Research Fund of the Research Grants Council of Hong Kong (Grant HKU 7764/07M).

References

 

DC FieldValueLanguage
dc.contributor.authorLin, Men_HK
dc.contributor.authorYiu, WHen_HK
dc.contributor.authorWu, HJen_HK
dc.contributor.authorChan, LYYen_HK
dc.contributor.authorLeung, JCKen_HK
dc.contributor.authorAu, WSen_HK
dc.contributor.authorChan, KWen_HK
dc.contributor.authorLai, KNen_HK
dc.contributor.authorTang, SCWen_HK
dc.date.accessioned2012-05-29T06:14:37Z-
dc.date.available2012-05-29T06:14:37Z-
dc.date.issued2012en_HK
dc.identifier.citationJournal Of The American Society Of Nephrology, 2012, v. 23 n. 1, p. 86-102en_HK
dc.identifier.issn1046-6673en_HK
dc.identifier.urihttp://hdl.handle.net/10722/148677-
dc.description.abstractInflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease fromother causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time- and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IβB/NF-βB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IβB/NF-βB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucose-treated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-βB activation, tubular CCL-2 expression, and interstitialmacrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathwaymay promote tubulointerstitial inflammation in diabetic nephropathy. Copyright © 2012 by the American Society of Nephrology.en_HK
dc.languageengen_US
dc.publisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.orgen_HK
dc.relation.ispartofJournal of the American Society of Nephrologyen_HK
dc.subject.meshAnimalsen_US
dc.subject.meshAntigens, Cd - Analysisen_US
dc.subject.meshAntigens, Differentiation, Myelomonocytic - Analysisen_US
dc.subject.meshCase-Control Studiesen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshChemotaxisen_US
dc.subject.meshDiabetes Mellitus, Experimental - Immunology - Metabolismen_US
dc.subject.meshDiabetic Nephropathies - Immunology - Metabolismen_US
dc.subject.meshGlucoseen_US
dc.subject.meshHmgb1 Protein - Metabolismen_US
dc.subject.meshHsp70 Heat-Shock Proteins - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshI-Kappa B Kinase - Metabolismen_US
dc.subject.meshKidney Cortex - Metabolismen_US
dc.subject.meshMacrophages - Physiologyen_US
dc.subject.meshMaleen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred C57blen_US
dc.subject.meshMice, Knockouten_US
dc.subject.meshMonocytes - Physiologyen_US
dc.subject.meshNf-Kappa B - Metabolismen_US
dc.subject.meshProtein Kinase C - Metabolismen_US
dc.subject.meshToll-Like Receptor 2 - Metabolismen_US
dc.subject.meshToll-Like Receptor 4 - Genetics - Metabolismen_US
dc.subject.meshUp-Regulationen_US
dc.titleToll-like receptor 4 promotes tubular inflammation in diabetic nephropathyen_HK
dc.typeArticleen_HK
dc.identifier.emailLeung, JCK:jckleung@hku.hken_HK
dc.identifier.emailChan, KW:hrmtckw@hku.hken_HK
dc.identifier.emailTang, SCW:scwtang@hku.hken_HK
dc.identifier.authorityLeung, JCK=rp00448en_HK
dc.identifier.authorityChan, KW=rp00330en_HK
dc.identifier.authorityTang, SCW=rp00480en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1681/ASN.2010111210en_HK
dc.identifier.pmid22021706-
dc.identifier.pmcidPMC3269929-
dc.identifier.scopuseid_2-s2.0-84862922902en_HK
dc.identifier.hkuros202605-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84862922902&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume23en_HK
dc.identifier.issue1en_HK
dc.identifier.spage86en_HK
dc.identifier.epage102en_HK
dc.identifier.isiWOS:000299151300014-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLin, M=55263956500en_HK
dc.identifier.scopusauthoridYiu, WH=15833609500en_HK
dc.identifier.scopusauthoridWu, HJ=55264644000en_HK
dc.identifier.scopusauthoridChan, LYY=35336076700en_HK
dc.identifier.scopusauthoridLeung, JCK=7202180349en_HK
dc.identifier.scopusauthoridAu, WS=7202383097en_HK
dc.identifier.scopusauthoridChan, KW=16444133100en_HK
dc.identifier.scopusauthoridLai, KN=55211267900en_HK
dc.identifier.scopusauthoridTang, SCW=7403437082en_HK
dc.identifier.citeulike10038264-

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