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Article: Additive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice

TitleAdditive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice
Authors
KeywordsB2-kinin receptor blockade
diabetic nephropathy
inflammation
PPAR-g agonist
renal pathology
signaling
uninephrectomy
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/
Citation
Laboratory Investigation, 2011, v. 91 n. 9, p. 1351-1362 How to Cite?
AbstractWe recently showed that the bradykinin B2 receptor (B2R) blocker icatibant (Icat) and the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Ros) exerted anti-inflammatory effects in renal tubular cells exposed to a diabetic milieu. This study aims to explore whether these effects can be translated to an experimental model of type 2 diabetic nephropathy (DN). db/db mice and their nondiabetic db/m littermates underwent sham operation or uninephrectomy (Unx) at 10 weeks and received vehicle (Veh), metformin (Met), Icat, Ros, or Icat plus Ros for 8 weeks before killing. Among the db/db group with Unx, mice that received Icat or Ros had significantly lower serum creatinine and albuminuria, which was further reduced when Icat and Ros were given in combination. These beneficial effects were not observed in the Met group that achieved similar glycemic control as Ros-treated animals. Likewise, the severity of reactive glomerular and proximal tubular hypertrophy, glomerulosclerosis, interstitial injury, cortical F4/80 and α-smooth muscle actin immunostaining, and CCL-2, ICAM-1 and TGF-Β overexpression were all attenuated by Icat and Ros, and these effects were enhanced when both agents were combined. Immunohistochemical staining confirmed the proximal tubular expression of CCL-2 (inflammation) and TGF-Β (fibrosis). Treatment with Icat was associated with decreased B2R, but increased, B1R expression, which was exaggerated in Unx animals. At the signaling level, Icat and Ros reduced extracellular signal-regulated kinase 1/2 and STAT1 activation, respectively. Our results suggest a deleterious role of the kallikrein-kinin system in murine-accelerated DN, which can be ameliorated by the B2R blocker Icat and enhanced by the addition of Ros. This calls for further evaluation of this novel therapeutic approach in more animal models of diabetic nephropathy. © 2011 USCAP, Inc All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/137414
ISSN
2014 Impact Factor: 3.676
2014 SCImago Journal Rankings: 1.656
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong KongHKU 7764/07M
Funding Information:

This study is supported by a General Research Fund of the Research Grants Council (Grant number: HKU 7764/07M) of Hong Kong. The bradykinin B2 receptor antagonist, icatibant (HOE 140), and the synthetic PPAR-gamma agonist, rosiglitazone were both kind gifts from Sanofi-Aventis Deutschland GmbH and GlaxoSmithKline (Compound Management Division, Stevenage, Herts, UK), respectively.

References

 

DC FieldValueLanguage
dc.contributor.authorTang, SCWen_HK
dc.contributor.authorChan, LYYen_HK
dc.contributor.authorLeung, JCKen_HK
dc.contributor.authorCheng, ASen_HK
dc.contributor.authorLan, HYen_HK
dc.contributor.authorLai, KNen_HK
dc.date.accessioned2011-08-26T14:24:34Z-
dc.date.available2011-08-26T14:24:34Z-
dc.date.issued2011en_HK
dc.identifier.citationLaboratory Investigation, 2011, v. 91 n. 9, p. 1351-1362en_HK
dc.identifier.issn0023-6837en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137414-
dc.description.abstractWe recently showed that the bradykinin B2 receptor (B2R) blocker icatibant (Icat) and the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Ros) exerted anti-inflammatory effects in renal tubular cells exposed to a diabetic milieu. This study aims to explore whether these effects can be translated to an experimental model of type 2 diabetic nephropathy (DN). db/db mice and their nondiabetic db/m littermates underwent sham operation or uninephrectomy (Unx) at 10 weeks and received vehicle (Veh), metformin (Met), Icat, Ros, or Icat plus Ros for 8 weeks before killing. Among the db/db group with Unx, mice that received Icat or Ros had significantly lower serum creatinine and albuminuria, which was further reduced when Icat and Ros were given in combination. These beneficial effects were not observed in the Met group that achieved similar glycemic control as Ros-treated animals. Likewise, the severity of reactive glomerular and proximal tubular hypertrophy, glomerulosclerosis, interstitial injury, cortical F4/80 and α-smooth muscle actin immunostaining, and CCL-2, ICAM-1 and TGF-Β overexpression were all attenuated by Icat and Ros, and these effects were enhanced when both agents were combined. Immunohistochemical staining confirmed the proximal tubular expression of CCL-2 (inflammation) and TGF-Β (fibrosis). Treatment with Icat was associated with decreased B2R, but increased, B1R expression, which was exaggerated in Unx animals. At the signaling level, Icat and Ros reduced extracellular signal-regulated kinase 1/2 and STAT1 activation, respectively. Our results suggest a deleterious role of the kallikrein-kinin system in murine-accelerated DN, which can be ameliorated by the B2R blocker Icat and enhanced by the addition of Ros. This calls for further evaluation of this novel therapeutic approach in more animal models of diabetic nephropathy. © 2011 USCAP, Inc All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/en_HK
dc.relation.ispartofLaboratory Investigationen_HK
dc.subjectB2-kinin receptor blockadeen_HK
dc.subjectdiabetic nephropathyen_HK
dc.subjectinflammationen_HK
dc.subjectPPAR-g agonisten_HK
dc.subjectrenal pathologyen_HK
dc.subjectsignalingen_HK
dc.subjectuninephrectomyen_HK
dc.titleAdditive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0023-6837&volume=91&issue=9&spage=1351&epage=1362&date=2011&atitle=Additive+renoprotective+effects+of+B2-kinin+receptor+blocker+and+PPAR-γ+agonist+in+uninephrectomized+db/db+mice-
dc.identifier.emailTang, SCW: scwtang@hku.hken_HK
dc.identifier.emailLeung, JCK: jckleung@hku.hken_HK
dc.identifier.emailLai, KN: knlai@hku.hken_HK
dc.identifier.authorityTang, SCW=rp00480en_HK
dc.identifier.authorityLeung, JCK=rp00448en_HK
dc.identifier.authorityLai, KN=rp00324en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/labinvest.2011.81en_HK
dc.identifier.pmid21537328en_HK
dc.identifier.scopuseid_2-s2.0-80052296926en_HK
dc.identifier.hkuros191029en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052296926&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume91en_HK
dc.identifier.issue9en_HK
dc.identifier.spage1351en_HK
dc.identifier.epage1362en_HK
dc.identifier.isiWOS:000294440500009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridTang, SCW=7403437082en_HK
dc.identifier.scopusauthoridChan, LYY=55182644100en_HK
dc.identifier.scopusauthoridLeung, JCK=7202180349en_HK
dc.identifier.scopusauthoridCheng, AS=21733421700en_HK
dc.identifier.scopusauthoridLan, HY=35783008500en_HK
dc.identifier.scopusauthoridLai, KN=7402135706en_HK
dc.identifier.citeulike9262926-

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