title: Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis.
abstract: Increased Src activity has been associated with the pathogenesis of renal tumors and some glomerular diseases, but its role in renal interstitial fibrosis remains elusive. To evaluate this, cultured renal interstitial fibroblasts (NRK-49F) were treated with PP1, a selective inhibitor of Src. This resulted in decreased expression of α-smooth muscle actin, fibronectin, and collagen I in response to serum, angiotension II, or transforming growth factor-β1 (TGF-β1). Silencing Src with siRNA also inhibited expression of those proteins. Furthermore, inhibition of Src activity blocked renal fibroblast proliferation. In a murine model of renal interstitial fibrosis induced by unilateral ureteral obstruction, the active form of Src (phopsho-Src Tyr416) was upregulated in both renal interstitial fibroblasts and renal tubular cells of the fibrotic kidney. Its inactivation reduced renal fibroblast activation and attenuated extracellular matrix protein deposition. Src inhibition also suppressed activation of TGF-β1 signaling, activation of the epidermal growth factor receptor and STAT3, and reduced the number of renal epithelial cells arrested at the G2/M phase of the cell cycle after ureteral obstruction. Thus, Src is an important mediator of renal interstitial fibroblast activation and renal fibrosis, and we suggest that Src is a potential therapeutic target for treatment of chronic renal fibrosis.
authors.affiliation: Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA; Departments of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Murugavel
authors.initials: M
authors.lastname: Ponnusamy
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Zhuang
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tolbert
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Bayliss
authors.affiliation: Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: szhuang@lifespan.org.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D024042:Collagen Type I / Q000378:metabolism; D004847:Epithelial Cells; D066246:ErbB Receptors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D059565:G2 Phase Cell Cycle Checkpoints; D020868:Gene Silencing; D007668:Kidney / Q000201:enzymology* / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D000199:Actins; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases
keywords: Src; epidermal growth factor receptor; renal fibrogenesis; renal interstitial fibroblasts; transforming growth factor-β1; α-smooth muscle actin