Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis

Shinong Wang, Mark C. Wilkes, Edward B Leof, Raimund Hirschberg

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor-β (TGF-β) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGF-β targets including p21-activated kinase-2 (PAK2), the abelson nonreceptor tyrosine kinase (c-Abl), and the mammalian target of rapamycin (mTOR) that are activated by TGF-β in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGF-β including PAK2, c-Abl, Akt, tuberin (TSC2), and mTOR are activated in experimental unilateral obstructive nephropathy in rats. Treatment with c-Abl or mTOR inhibitors, imatinib mesylate and rapamycin, respectively, each blocks noncanonical (non-smad) TGF-β pathways in the kidney in vivo and diminishes the number of interstitial fibroblasts and myofibroblasts as well as the interstitial accumulation of extracellular matrix proteins. These findings indicate that noncanonical TGF-β pathways are activated during the early and rapid renal fibrogenesis of obstructive nephropathy. Moreover, the current findings suggest that combined inhibition of key regulators of these non-smad TGF-β pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume298
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Transforming Growth Factors
Kidney
Sirolimus
p21-Activated Kinases
Fibroblasts
Myofibroblasts
Extracellular Matrix Proteins
Clinical Protocols
mechanistic target of rapamycin complex 1
Chronic Renal Insufficiency
Protein-Tyrosine Kinases
Renal Insufficiency
Fibrosis
Epithelial Cells
Cytokines

Keywords

  • Imatinib
  • mTOR
  • Rapamycin

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Urology

Cite this

Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis. / Wang, Shinong; Wilkes, Mark C.; Leof, Edward B; Hirschberg, Raimund.

In: American Journal of Physiology - Renal Physiology, Vol. 298, No. 1, 01.2010.

Research output: Contribution to journalArticle

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