Wnt/ b -catenin signaling and renin-angiotensin system Youhua Liu, - - PowerPoint PPT Presentation

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wnt b catenin signaling and renin angiotensin system
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Wnt/ b -catenin signaling and renin-angiotensin system Youhua Liu, - - PowerPoint PPT Presentation

Nov 24, 2022 215 likes •525 views

Wnt/ b -catenin signaling and renin-angiotensin system Youhua Liu, Ph.D Department of Pathology, University of Pittsburgh School of Medicine; State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University Canonical

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Wnt/b-catenin signaling and renin-angiotensin system

Youhua Liu, Ph.D

Department of Pathology, University of Pittsburgh School of Medicine; State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University

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Moon et al, 2004

Canonical Wnt/b-catenin signaling

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b-Catenin is primarily induced in tubular epithelium of fibrotic kidneys

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Tubular induction of Wnt1 and Wnt4 are common finding in human CKD

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5

Activation of β-catenin human CKD

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Blockade of Shh or Wnt/b-catenin signaling inhibits renal fibrosis

Mode of action CPN Smo

JASN 2012 JASN 2014

DKK1 LRP5/6 JASN 2009 Paricalcitol VDR JASN 2011 ICG-001 CBP JASN 2011 Klotho Wnt JASN 2013 ICG-001 CBP JASN 2014

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Wnt/b-catenin downstream targets

JASN 2009 JASN 2012 JASN 2015 JBC 2011

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Wnt/b-catenin and RAS activation

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Up-regulation of multiple components of the renin- angiotensin system in CKD

ACEI ARB

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Inhibition of RAS upregulates renin expression in vivo

AGT Angiotensin I Angiotensin II Renin ACE

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Could we simultaneously targets/inhibits multiple components of RAS?

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Wnt/b-catenin signaling induces all components of renin-angiotensin system

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Wnt/b-catenin induces all components of RAS in vitro and localization of b-catenin and RAS in vivo

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ICG-001, a specific small molecule b-catenin inhibitor, simultaneously inhibits multiple components of RAS

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Blockade of b-catenin signaling by ICG-001 reverses proteinuria and kidney injury

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Blockade of b-catenin signaling by ICG-001 attenuates kidney fibrotic lesions

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Blockade of b-catenin signaling by ICG-001 targets the expression of multiple RAS components in vivo

One stone kills multiple birds?

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Therapeutic protocol

ICG-001, 3 times/week, 5 mg/kg body wt

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ICG-001 normalizes blood pressure in rats

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ICG-001 represses RAS activation in rat remnant kidney model

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ICG-001 inhibits renal fibrosis in rat remnant kidney model

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Direct comparison of the therapeutic efficacy between Wnt/β-catenin inhibitor and RAS blocker

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ICG-001 is more effective than RAS blocker in preventing AKI-CKD progression

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ICG-001 completely inhibits RAS expression

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RAS blocker therapy upregulates renin expression

1) Sham control 2) UIRI + vehicle 3) UIRI + trandolapril (3 mg/kg/day, oral) 4) UIRI + trandolapril (3 mg/kg/day, oral) + losartan (10 mg/kg/day, oral) 5) UIRI+ ICG-001（5 mg/kg/day, I.P.）

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ICG-001 is more effective than RAS blocker in ameliorating ADR nephropathy

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ICG-001, but not RAS blocker, completely inhibits RAS expression

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Renin promotes renal fibrosis by Ang II-independent mechanism

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Summary

Wnt/b-catenin

ARB ACEI

Fibrosis Inflammation Hypertension ICG-001

Summary

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Acknowledgments

Roderick Tan Dong Zhou Haiyan Fu Southern Medical University University of Pittsburgh