Basic fibroblast growth factor (FGF-2) plays a role in renal fibrogenesis though 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 to 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 when compared to 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-1 and PKC-2, however only inhibition of PKC-1 but not PKC-2 led to a significant decrease of FGF-2 levels. Relevance of the culture findings and functional association was corroborated by colocalisation of FGF-2 and PKC- in human diabetic kidneys in vivo. High glucose stimulated fibronectin synthesis and secretion, which could be substantially prevented by inhibition of PKC-1 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.