Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts.
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-beta1 and PKC-beta2; however, only inhibition of PKC-beta1 but not PKC-beta2 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-beta in human diabetic kidneys in vivo. High glucose stimulated fibronectin synthesis and secretion, which could be substantially prevented by inhibition of PKC-beta1 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.
Vasko
Radovan
R
Department of Nephrology and Rheumatology, Georg-August-Univ. Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany. rvasko@inbox.com
Koziolek
Michael
M
Ikehata
Masami
M
Rastaldi
Maria Pia
MP
Jung
Klaus
K
Schmid
Holger
H
Kretzler
Matthias
M
Müller
Gerhard Anton
GA
Strutz
Frank
F
D001706:Biopsy; D049109:Cell Proliferation / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007668:Kidney / Q000166:cytology* / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D005353:Fibronectins; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose