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Conference Paper: Dual blockade of Angiotensin II and prorenin receptors ameliorates podocytic apoptosis in IgA nephropathy through inhibition of the notch signaling pathway

TitleDual blockade of Angiotensin II and prorenin receptors ameliorates podocytic apoptosis in IgA nephropathy through inhibition of the notch signaling pathway
Authors
Issue Date2012
PublisherAmerican Society of Nephrology. The Journal's web site is located at https://www.asn-online.org/abstracts/
Citation
Kidney Week 2012, San Diego, CA., 30 October-4 November 2012. In Journal of the American Society of Nephrology, 2012, v. 23, p. 322A, abstract no. TH-PO959 How to Cite?
AbstractBACKGROUND: Glomerulo-podocytic communication plays an important role in podocytic injury in IgA nephropathy (IgAN). We examined the roles of podocytic angiotensin II receptor subtype 1 (ATR1) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. METHODS: Conditioned medium was prepared from growth arrested mesangial cells incubated with polymeric IgA from patients (IgA-medium, n=28) or controls (Ctl-medium, n=25). An immortalized human podocyte cell line was used to study the regulation of ATR1, PRR, TNF-α and TGF-β by IgA-medium. Expression of p53 and cleaved caspase 3 was used as functional readout of podocytic apoptosis. RESULTS: Podocytic expression of ATR1 and PRR were up-regulated by IgA-HMC medium dose and time dependently (p<0.01). There was increased expression of ATR1 and release of TGF-β, but not PRR, by podocyte cultured with TNF-α (p<0.05). The IgA-medium, TNF-α or TGF-β induced podocytic apoptosis. We further examined the anti-apoptotic effects of mono- or combined blockade of ATR1, PRR, TNF-α and TGF-β; with losartan, PRR siRNA transfection and anti-TNF-α and anti-TGF-β antibodies. Mono-blockade of ATR1, PRR or TNF-α partially reduced podocytic apoptosis. Dual blockade of ATR1 and PRR, or mono-blockade with anti-TGF-β, effectively rescued podocyte from IgA-medium induced apoptosis. Interestingly, IgA-medium or TGF-β up-regulated the expression of Jag1, notch1 and Hes1 by podocyte. The related podocytic apoptosis was abolished by the γ-secretase blocker, suggesting the important role of notch signaling pathway in this apoptotic process. Blockade of PRR or ATR1 decreased the IgA-medium induced TGF-β release and notch1 expression by podocyte, and these TGF-β release and notch1 expression were further reduced through dual blockade of ATR1 and PRR. CONCLUSIONS: Our data suggest that the TGF-β and notch signaling pathway are the key players in podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Targeting the notch signaling pathway, AT1R and prorenin receptor could be a potential therapeutic option to reduce the podocytic injury in IgAN.
DescriptionThursday Poster Presentation - Pathobiology: Basic/Experimental Pathology - I: no. TH-PO959
Persistent Identifierhttp://hdl.handle.net/10722/186847
ISSN
2015 Impact Factor: 8.491
2015 SCImago Journal Rankings: 4.699

 

DC FieldValueLanguage
dc.contributor.authorLeung, JCKen_US
dc.contributor.authorLim, AIen_US
dc.contributor.authorChan, LYYen_US
dc.contributor.authorTang, SCWen_US
dc.contributor.authorLai, KNen_US
dc.date.accessioned2013-08-20T12:21:13Z-
dc.date.available2013-08-20T12:21:13Z-
dc.date.issued2012en_US
dc.identifier.citationKidney Week 2012, San Diego, CA., 30 October-4 November 2012. In Journal of the American Society of Nephrology, 2012, v. 23, p. 322A, abstract no. TH-PO959en_US
dc.identifier.issn1046-6673-
dc.identifier.urihttp://hdl.handle.net/10722/186847-
dc.descriptionThursday Poster Presentation - Pathobiology: Basic/Experimental Pathology - I: no. TH-PO959-
dc.description.abstractBACKGROUND: Glomerulo-podocytic communication plays an important role in podocytic injury in IgA nephropathy (IgAN). We examined the roles of podocytic angiotensin II receptor subtype 1 (ATR1) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. METHODS: Conditioned medium was prepared from growth arrested mesangial cells incubated with polymeric IgA from patients (IgA-medium, n=28) or controls (Ctl-medium, n=25). An immortalized human podocyte cell line was used to study the regulation of ATR1, PRR, TNF-α and TGF-β by IgA-medium. Expression of p53 and cleaved caspase 3 was used as functional readout of podocytic apoptosis. RESULTS: Podocytic expression of ATR1 and PRR were up-regulated by IgA-HMC medium dose and time dependently (p<0.01). There was increased expression of ATR1 and release of TGF-β, but not PRR, by podocyte cultured with TNF-α (p<0.05). The IgA-medium, TNF-α or TGF-β induced podocytic apoptosis. We further examined the anti-apoptotic effects of mono- or combined blockade of ATR1, PRR, TNF-α and TGF-β; with losartan, PRR siRNA transfection and anti-TNF-α and anti-TGF-β antibodies. Mono-blockade of ATR1, PRR or TNF-α partially reduced podocytic apoptosis. Dual blockade of ATR1 and PRR, or mono-blockade with anti-TGF-β, effectively rescued podocyte from IgA-medium induced apoptosis. Interestingly, IgA-medium or TGF-β up-regulated the expression of Jag1, notch1 and Hes1 by podocyte. The related podocytic apoptosis was abolished by the γ-secretase blocker, suggesting the important role of notch signaling pathway in this apoptotic process. Blockade of PRR or ATR1 decreased the IgA-medium induced TGF-β release and notch1 expression by podocyte, and these TGF-β release and notch1 expression were further reduced through dual blockade of ATR1 and PRR. CONCLUSIONS: Our data suggest that the TGF-β and notch signaling pathway are the key players in podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Targeting the notch signaling pathway, AT1R and prorenin receptor could be a potential therapeutic option to reduce the podocytic injury in IgAN.-
dc.languageengen_US
dc.publisherAmerican Society of Nephrology. The Journal's web site is located at https://www.asn-online.org/abstracts/-
dc.relation.ispartofJASN Abstract Supplementen_US
dc.titleDual blockade of Angiotensin II and prorenin receptors ameliorates podocytic apoptosis in IgA nephropathy through inhibition of the notch signaling pathwayen_US
dc.typeConference_Paperen_US
dc.identifier.emailLeung, JCK: jckleung@hku.hken_US
dc.identifier.emailChan, LYY: yychanb@hku.hken_US
dc.identifier.emailTang, SCW: scwtang@hku.hken_US
dc.identifier.emailLai, KN: knlai@hku.hken_US
dc.identifier.authorityLeung, JCK=rp00448en_US
dc.identifier.authorityTang, SCW=rp00480en_US
dc.identifier.authorityLai, KN=rp00324en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros220820en_US
dc.identifier.volume23en_US
dc.identifier.spage322A, abstract no. THen_US
dc.identifier.epagePO959en_US
dc.publisher.placeUnited States-

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