Noncanonical TGF-beta pathways, mTORC1 and Abl, in renal interstitial fibrogenesis.
Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor-beta (TGF-beta) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGF-beta 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-beta in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGF-beta 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-beta 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-beta 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-beta pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90509, USA.
Shinong
S
Wang
Mark C
MC
Wilkes
Edward B
EB
Leof
Raimund
R
Hirschberg
D000818:Animals; D001549:Benzamides; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D000068877:Imatinib Mesylate; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications
D001549:Benzamides; C519510:Crtc1 protein, rat; D010879:Piperazines; D011743:Pyrimidines; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D020123:Sirolimus