Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts

Radovan Vasko, Michael Koziolek, Masami Ikehata, Maria Pia Rastaldi, Klaus Jung, Holger Schmid, Matthias Kretzler, Gerhard Anton Müller, Frank Strutz

Research output: Contribution to journalArticlepeer-review

Abstract

Basic fibroblast growth factor (FGF-2) plays a role in renal fibrogenesis, although its potential implications for tubulointerstitial involvement in diabetic nephropathy are unknown. We evaluated the expression of FGF-2 in kidney biopsies from patients with diabetic nephropathy and studied the mechanisms of its induction in human renal fibroblasts under hyperglycemia. Tubulointerstitial expression of FGF-2 was significantly upregulated in diabetic nephropathy compared with control kidneys with a good correlation to the degree of the injury. Fibroblasts cultivated in high glucose displayed increased FGF-2 mRNA as well as protein synthesis and secretion compared with normal glucose. Proliferation rates under hyperglycemia were significantly higher and could be almost completely inhibited by addition of a neutralizing FGF-2 antibody. Alterations in proliferation were associated with changes in p27 kip1 expression. Hyperglycemia induced the expression of PKC-β1 and PKC-β2; however, only inhibition of PKC-β1 but not PKC-β2 led to a significant decrease of FGF-2 levels. Relevance of the culture findings and functional association was corroborated by colocalization of FGF-2 and PKC-β in human diabetic kidneys in vivo. High glucose stimulated fibronectin synthesis and secretion, which could be substantially prevented by inhibition of PKC-β1 and to a lesser extent by inhibiting the FGF-2. Expression of active phosphorylated form of p38 mitogen-activated protein kinase was upregulated under hyperglycemia; however, its inhibition had no effects on FGF-2 synthesis. Our results implicate a role of FGF-2 in high glucose-altered molecular signaling in pathogenesis of diabetic renal disease.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume296
Issue number6
DOIs
Publication statusPublished - Jun 2009

Keywords

  • Fibronectin synthesis
  • Protein kinase C
  • Renal biopsy
  • Tubulointerstitial involvement

ASJC Scopus subject areas

  • Physiology
  • Urology

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