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Article: Additive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice
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TitleAdditive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice
 
AuthorsTang, SCW1
Chan, LYY1
Leung, JCK1
Cheng, AS1
Lan, HY2
Lai, KN1
 
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/
 
CitationLaboratory Investigation, 2011, v. 91 n. 9, p. 1351-1362 [How to Cite?]
DOI: http://dx.doi.org/10.1038/labinvest.2011.81
 
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.
 
ISSN0023-6837
2012 Impact Factor: 3.961
2012 SCImago Journal Rankings: 1.448
 
DOIhttp://dx.doi.org/10.1038/labinvest.2011.81
 
ISI Accession Number IDWOS:000294440500009
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorTang, SCW
 
dc.contributor.authorChan, LYY
 
dc.contributor.authorLeung, JCK
 
dc.contributor.authorCheng, AS
 
dc.contributor.authorLan, HY
 
dc.contributor.authorLai, KN
 
dc.date.accessioned2011-08-26T14:24:34Z
 
dc.date.available2011-08-26T14:24:34Z
 
dc.date.issued2011
 
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.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationLaboratory Investigation, 2011, v. 91 n. 9, p. 1351-1362 [How to Cite?]
DOI: http://dx.doi.org/10.1038/labinvest.2011.81
 
dc.identifier.citeulike9262926
 
dc.identifier.doihttp://dx.doi.org/10.1038/labinvest.2011.81
 
dc.identifier.epage1362
 
dc.identifier.hkuros191029
 
dc.identifier.isiWOS:000294440500009
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.

 
dc.identifier.issn0023-6837
2012 Impact Factor: 3.961
2012 SCImago Journal Rankings: 1.448
 
dc.identifier.issue9
 
dc.identifier.openurl
 
dc.identifier.pmid21537328
 
dc.identifier.scopuseid_2-s2.0-80052296926
 
dc.identifier.spage1351
 
dc.identifier.urihttp://hdl.handle.net/10722/137414
 
dc.identifier.volume91
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofLaboratory Investigation
 
dc.relation.referencesReferences in Scopus
 
dc.subjectB2-kinin receptor blockade
 
dc.subjectdiabetic nephropathy
 
dc.subjectinflammation
 
dc.subjectPPAR-g agonist
 
dc.subjectrenal pathology
 
dc.subjectsignaling
 
dc.subjectuninephrectomy
 
dc.titleAdditive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice
 
dc.typeArticle
 
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Author Affiliations
  1. Queen Mary Hospital Hong Kong
  2. Chinese University of Hong Kong