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Experimental Biology and Medicine 227:171-181 (2002)
© 2002 Society for Experimental Biology and Medicine

ORIGINAL ARTICLE

TGF-ß1 Is an Autocrine Mediator of Renal Tubular Epithelial Cell Growth and Collagen IV Production

Joseph P. Grande*,{dagger},1, Gina M. Warner*, Henry J. Walker*, Ahad N. K. Yusufi*, Jingfei Cheng*, Catherine E. Gray*, Jeffrey B. Kopp{ddagger} and Karl A. Nath*,{dagger}

* Renal Pathophysiology Laboratory, Department of Laboratory Medicine and Pathology, and
{dagger} Division of Nephrology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905; and
{ddagger} Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Recent studies in cultured cells have provided evidence that a variety of pathobiologic stimuli, including high glucose, angiotensin II, and thromboxane A2, trigger a signaling pathway leading to autocrine induction of TGF-ß1. TGF-ß1 production through this pathway may profoundly affect cell growth, matrix synthesis, and response to injury. This study examines the role of autocrine versus exogenously added TGF-ß1 in cellular proliferation and collagen IV production, critical targets of TGF-ß1 signaling, using renal cells derived from TGF-ß1 knockout (KO) animals or wild-type (WT) controls. Growth of WT and KO cells was assessed by cell counting and [3H]thymidine uptake. Basal and TGF-ß1-stimulated collagen production was assessed by Northern and Western blotting; transcriptional activity of the {alpha}1(IV) collagen gene was assessed by transient transfection analysis. KO cells grew at a faster rate than WT cells carefully matched for plating density and passage number. This increased growth rate was paralleled by increases in [3H]thymidine uptake. KO cells expressed lower levels of the cell cycle inhibitors p21 and p27 than WT cells. KO cells failed to express TGF-ß1, as expected. Basal TGF-ß3 mRNA levels were higher in KO cells than in WT cells. WT cells expressed higher basal levels of TGF-ß2 mRNA than KO cells. Basal {alpha}1(IV) and {alpha}2(IV) collagen mRNA and protein expression were significantly lower in KO cells than WT cells. Administration of exogenous TGF-ß1 induced collagen IV production in both KO and WT cells. Although basal transcriptional activity of an {alpha}1(IV) collagen-CAT construct was lower in KO cells than WT cells, administration of exogenous TGF-ß1 was associated with significant increases in transcriptional activity of this construct in both KO and WT cells. These studies provide evidence that autocrine production of TGF-ß1 may play a critical role in regulation of growth and basal collagen IV production by renal tubular epithelial cells.

Key Words: TGF-ß1 • proliferation • collagen IV • kidney • tubular epithelial cells




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