Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Harvard University

Details

Original languageEnglish (US)
Pages (from-to)F471-F484
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number4
StatusPublished - Aug 15 2014
Peer-reviewedYes

Abstract

Fibrinogen (Fg) has been implicated in the pathogenesis of several fibrotic disorders by acting as a profibrotic ligand for a variety of cellular surface receptors and by modulating the provisional fibrin matrix formed after injury. We demonstrated increased renal Fg expression after unilateral ureteral obstruction and folic acid (FA) nephropathy in mice, respectively. Urinary Fg excretion was also increased in FA nephropathy. Using in vitro and in vivo approaches, our results suggested that IL-6 mediates STAT3 activation in kidney fibrosis and that phosphorylated (p)STAT3 binds to Fgα, Fgβ, and Fgγ promoters in the kidney to regulate their transcription. Genetically modified Fg heterozygous mice (~75% of normal plasma Fg levels) exhibited only 3% kidney interstitial fibrosis and tubular atrophy after FA nephropathy compared with 24% for wild-type mice. Fibrinogenolysis through Ancrod administration after FA reduced interstitial fibrosis more than threefold compared with vehicle-treated control mice. Mechanistically, we show that Fg acts synergistically with transforming growth factor (TGF)-β1 to induce fibroblast proliferation and activates TGF-β1/pSMAD2 signaling. This study offers increased understanding of Fg expression and molecular interactions with TGF-β1 in the progression to kidney fibrosis and, importantly, indicates that fibrinogenolytics like Ancrod present a treatment opportunity for a yet intractable disease.

    Research areas

  • Ancrod, Chronic kidney disease, Fibrinogen, Kidney fibrosis

Citation formats

APA

Craciun, F. L., Ajay, A. K., Hoffmann, D., Saikumar, J., Fabian, S. L., Bijol, V., ... Vaidya, V. S. (2014). Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis. American Journal of Physiology - Renal Physiology, 307(4), F471-F484. https://doi.org/10.1152/ajprenal.00189.2014

Harvard

Craciun, FL, Ajay, AK, Hoffmann, D, Saikumar, J, Fabian, SL, Bijol, V, Humphreys, BD & Vaidya, VS 2014, 'Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis', American Journal of Physiology - Renal Physiology, vol. 307, no. 4, pp. F471-F484. https://doi.org/10.1152/ajprenal.00189.2014