Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury

Sarah Huen, Gilbert W. Moecke, Lloyd G. Cantley

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume305
Issue number4
DOIs
StatePublished - May 8 2013

Fingerprint

Transforming Growth Factors
Reperfusion
Fibrosis
Ischemia
Macrophages
Kidney
Wounds and Injuries
Cytophagocytosis
Kidney Diseases
Myeloid Cells
Reperfusion Injury
Chronic Renal Insufficiency
Innate Immunity
Cicatrix
Messenger RNA

Keywords

  • Ischemia-reperfusion
  • Macrophage
  • Renal fibrosis
  • TGF-β1

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

@article{1dd76aa08dba4ad599c8811ca970d4f9,
title = "Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury",
abstract = "Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.",
keywords = "Ischemia-reperfusion, Macrophage, Renal fibrosis, TGF-β1",
author = "Sarah Huen and Moecke, {Gilbert W.} and Cantley, {Lloyd G.}",
year = "2013",
month = "5",
day = "8",
doi = "10.1152/ajprenal.00624.2012",
language = "English (US)",
volume = "305",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury

AU - Huen, Sarah

AU - Moecke, Gilbert W.

AU - Cantley, Lloyd G.

PY - 2013/5/8

Y1 - 2013/5/8

N2 - Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

AB - Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

KW - Ischemia-reperfusion

KW - Macrophage

KW - Renal fibrosis

KW - TGF-β1

UR - http://www.scopus.com/inward/record.url?scp=84881636594&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881636594&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00624.2012

DO - 10.1152/ajprenal.00624.2012

M3 - Article

C2 - 23761668

AN - SCOPUS:84881636594

VL - 305

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 4

ER -