Divergent roles of Smad3 and PI3-kinase in murine adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis

Gal Finer, H. William Schnaper, Yashpal S. Kanwar, Xiaoyan Liang, Herbert Y. Lin, Tomoko Hayashida*

*Corresponding author for this work

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Multiple transforming growth factor (TGF)-Β-induced fibrogenic signals have been described in vitro. To evaluate mechanisms in vivo, we used an adriamycin nephropathy model in 129x1/Svj mice that display massive proteinuria by days 5 to 7 and pathological findings similar to human focal segmental glomerulosclerosis by day 14. TGF-Β mRNA expression increased after day 7 along with nuclear translocation of the TGF-Β receptor-specific transcription factor Smad3. Inhibiting TGF-Β prevented both pathological changes and type-I collagen and fibronectin mRNA expression, but proteinuria persisted. Renal Akt was phosphorylated in adriamycin-treated mice, suggesting PI3-kinase activation. Expression of mRNA for the p110γ isozyme of PI3-kinase was specifically increased and p110γ colocalized with nephrin by immunohistochemistry early in disease. Nephrin levels subsequently decreased. Inhibition of p110γ by AS605240 preserved nephrin expression and prevented proteinuria. In cultured podocytes, adriamycin stimulated p110γ expression. AS605240, but not a TGF-Β receptor kinase inhibitor, prevented adriamycin-induced cytoskeletal disorganization and apoptosis, supporting a role for p110γ in podocyte injury. AS605240, at a dose that decreased proteinuria, prevented renal collagen mRNA expression in vivo but did not affect TGF-Β-stimulated collagen induction in vitro. Thus, PI3-kinase p110γ mediates initial podocyte injury and proteinuria, both of which precede TGF-Β-mediated glomerular scarring.

Original languageEnglish (US)
Pages (from-to)525-536
Number of pages12
JournalKidney international
Volume82
Issue number5
DOIs
StatePublished - Sep 1 2012

Keywords

  • TGF-β
  • cell signaling
  • fibrosis
  • glomerulosclerosis
  • podocyte

ASJC Scopus subject areas

  • Nephrology

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