Matsui, FutoshiBabitz, Stephen A.Rhee, AudreyHile, Karen L.Zhang, HongjiMeldrum, Kirstan K.2018-06-042018-06-042017-01-01Matsui, F., Babitz, S. A., Rhee, A., Hile, K. L., Zhang, H., & Meldrum, K. K. (2017). Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production. American Journal of Physiology - Renal Physiology, 312(1), F25–F32. http://doi.org/10.1152/ajprenal.00311.2016https://hdl.handle.net/1805/16351STAT3 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.en-USPublisher PolicyEpithelial mesenchymal transitionKidneyMatrix metalloproteinase-9Matrix metalloproteinasesMesenchymal stem cellSignal transducer and activator of transcription-3Signal transducers and activators of transcriptionUnilateral ureteral obstructionUreteral obstructionArticle