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J Am Soc Nephrol 10:1891-1899, 1999
© 1999 American Society of Nephrology

REGULAR ARTICLES

High Glucose Stimulates Proliferation and Collagen Type I Synthesis in Renal Cortical Fibroblasts

Mediation by Autocrine Activation ofTGF-ß

DONG CHEOL HAN, MOTOHIDE ISONO, BRENDA B. HOFFMAN and FUAD N. ZIYADEH

Renal-Electrolyte and Hypertension Division and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Correspondence to Dr. Fuad N. Ziyadeh, Renal-Electrolyte Division, University of Pennsylvania, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-6144. Phone: 215-662-7900; Fax: 215-898-0189; E-mail: ziyadeh{at}mail.med.upenn.edu

Abstract

Abstract. Renal tubular epithelial cells and interstitial fibroblasts are active participants in tubulointerstitial fibrosis, the best correlate of decreased glomerular filtration in diabetic nephropathy. It was reported previously that high ambient glucose stimulates transforming growth factor-ß (TGF-ß) mRNA and bioactivity, promotes cellular hypertrophy, and increases collagen synthesis in proximal tubular cells. This study evaluates the effects of high glucose and TGF-ß on the behavior of murine renal cortical fibroblasts (TFB) in culture. High glucose (450 mg/dl) significantly increased [3H]-thymidine incorporation (by 60 to 80% after 24 to 72 h) and cell number, without significantly increasing cell death when compared with normal glucose (100 mg/dl). There also was a transient increase in the mRNA of the c-myc and egr-1 early-response genes. Exogenous TGF-ß1 was promitogenic rather than antiproliferative in contrast to other renal cell types. Northern blot analysis demonstrated constitutive expression of TGF-ß1, -ß2, and -ß3 transcripts. Exposure to high glucose increased all three TGF-ß isoforms in a time-dependent manner. High glucose as well as exogenous TGF-ß1 also increased [3H]-proline incorporation, {alpha}2(I) collagen mRNA, and type I collagen protein (measured by immunoassay). Treatment with a neutralizing pan-selective monoclonal anti-TGF-ß antibody markedly attenuated the stimulation by high ambient glucose of thymidine incorporation, TGF-ß1 mRNA, and type I collagen mRNA and protein levels. It is concluded that high ambient glucose and exogenous TGF-ß1 share similar actions on renal fibroblasts. Moreover, the stimulation of cell proliferation and collagen type I synthesis in these cells by high ambient glucose are mediated by activation of an autocrine TGF-ß system.




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