title: Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production.
abstract: STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction-induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 × 106/rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson's trichrome), fibronectin, α-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, α-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction-induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production.
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Matsui
authors.affiliation: Division of Pediatric Urology, Helen DeVos Children's Hospital, Grand Rapids, Michigan.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Babitz
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Audrey
authors.initials: A
authors.lastname: Rhee
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Hile
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Hongji
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Urology, Helen DeVos Children's Hospital, Grand Rapids, Michigan Kirstan.Meldrum@helendevoschildrens.org.
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; D005353:Fibronectins; C520337:NSC 74859; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: epithelial mesenchymal transition; kidney; matrix metalloproteinase-9; matrix metalloproteinases; mesenchymal stem cell; signal transducer and activator of transcription-3; signal transducers and activators of transcription; unilateral ureteral obstruction; ureteral obstruction