BSC-1 growth inhibitor transforms a mitogenic stimulus into a hypertrophic stimulus for renal proximal tubular cells: relationship to Na+/H+ antiport activity.

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Abstract
Renal hypertrophy is characterized by an increase in cell size and protein content with minimal hyperplasia. The mechanisms of control of this pattern of cell growth have not been determined. The present studies examined whether the growth inhibitor elaborated by BSC-1 kidney epithelial cells (GI), which has nearly identical biological properties to transforming growth factor .beta. (TGF-.beta.), could transform a mitogenic stimulus into a hypertrophic stimulus for rabbit renal proximal tubular cells in primary culture. Insulin (10 .mu.g/ml) plus hydrocortisone (50 nM) increased the amount of protein per cell, cell volume, and [3H]thymidine incorporation at 24 and 48 hr in these cells. GI/TGF-.beta. (10 units/ml) led to a minimal stimulation of [3H]thymidine incorporation. When added together with insulin plus hydrocortisone, GI/TGF-.beta. inhibited the stimulatory effect of these mitogens on [3H]thymidine incorporation but did not block the increase in protein per cell and cell volume.sbd.i.e., the cells underwent hypertrophy. The fact that this pattern persisted for 48 hr indicated that GI/TGF-.beta. exerted a prolonged inhibitory effect on mitogenic-stimulated DNA synthesis rather than delaying its onset. Amiloride-sensitive Na+ uptake (inditative of Na+/H+ antiport activity) correlated with protein per cell and cell volume rather than with DNA synthesis. P60 gel chromatographic fractionation of conditioned medium harvested from proximal tubular cells yielded a fraction that inhibited [3H]thymidine incorporation in BSC-1 cells and CCL 64 cells; the relative inhibitory activity on these cell lines and the chromatographic behavior were similar to those observed with GI/TGF-.beta.. These studies indicate that the control cell size may be regulated by autocrine mechanisms mediated by the elaboration of growth inhibitory factors that alter the pattern of the growth response to mitogens.

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