Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

Florin L. Craciun, Amrendra K. Ajay, Dana Hoffmann, Janani Saikumar, Steven L. Fabian, Vanesa Bijol, Benjamin D. Humphreys, Vishal S. Vaidya

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)F471-F484
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number4
DOIs
StatePublished - Aug 15 2014
Externally publishedYes

Keywords

  • Ancrod
  • Chronic kidney disease
  • Fibrinogen
  • Kidney fibrosis

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    Craciun, F. L., Ajay, A. K., Hoffmann, D., Saikumar, J., Fabian, S. L., Bijol, V., Humphreys, B. D., & 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