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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/F1452    most recent 90352.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Vasko, R. Articles by Strutz, F. PubMed PubMed Citation Articles by Vasko, R. Articles by Strutz, F.

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

¹Department of Nephrology and Rheumatology, ²Department of Medical Statistics, Georg-August-University Goettingen, Goettingen; ³Medical Policlinic, Ludwig Maximilian University, Munich, Germany; and ⁴Fondazione D'Amico and Fondazione IRCCS Policlinico, Milan, Italy

Submitted 9 June 2008 ; accepted in final form 5 March 2009

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.

tubulointerstitial involvement; fibronectin synthesis; protein kinase C; renal biopsy