TGF-BETA(1) DISSOCIATES HUMAN PROXIMAL TUBULE CELL-GROWTH AND NA-H+ EXCHANGE ACTIVITY()

Stimulation of proximal tubule cell (PTC) growth in a variety of physi ological and pathological renal conditions is preceded by increased re nal production of transforming growth factor-beta(1) (TGF-beta(1)) and by augmented tubular sodium transport via activated sodium hydrogen e xchange (NHE). Since TGF-beta 1 has been shown to be an important para crine and autocrine regulator of PTC growth, the hypothesis that TGF-b eta(1) modulates basal and mitogen-stimulated PTC growth via an effect on NHE activity was examined. Confluent, quiescent, human PTC were in cubated for 23 hours in serum-free media containing vehicle (control) or 1 ng/ml TGF-beta 1, in the presence or absence of 100 ng/ml insulin -like growth factor-1 (IGF-I). Under basal conditions, TGF-beta(1) inh ibited thymidine incorporation (73.5 +/- 7.3% of control, P < 0.05), b ut exerted no effect on cellular protein content (97.4 +/- 10.7% of co ntrol), an index of hypertrophy. There was no significant alteration o f NHE activity, measured as ethylisopropylamiloride (EIPA)-sensitive H + efflux (2.72 +/- 0.50 vs, control 3.26 +/- 0.68 mmol/liter/min) or N a-22(+) influx (2.20 +/- 0.23 vs. control 2.19 +/- 0.19 nmol/mg protei n/min). When co-incubated with IGF-I, TGF-beta(1) induced significant PTC hypertrophy (116.9 +/- 8.2% of control, P < 0.05), which was not s een with either agent alone. TGF-beta(1) counteracted the stimulator, effect of IGF-I on DNA synthesis (TGF-beta(1) + IGF-I 103.0 +/- 7.3% v s. IGF-I alone 181.2 +/- 30.3% of control, P < 0.05), but did not affe ct IGF-I-stimulated EIPA-sensitive Na-22(+) influx (3.63 +/- 0.63 vs. IGF-I alone 3.67 +/- 0.50 nmol/mg protein/min, P = NS, both vs, contro l 2.19 +/- 0.19 nmol/mg protein/min, P < 0.05). Similar results were o btained when NHE activity was measured as EIPA-sensitive H+ efflux. Mo reover, the kinetics of NHE activation by the combination of TGF-beta( 1) and IGF-I (involving an increase in V-max) were identical to that p reviously found for PTC exposed to IGF-I alone. The study demonstrates that TGF-beta(1) elicits distinct PTC growth responses in the presenc e and absence of IGF-I. without modification of NHE activity. The comb ination of predominant PTC hypertrophy and enhanced proximal tubule Na + reabsorption found in many conditions that are associated with renal growth is likely to require the integrated actions of both TGF-beta(1 ) and IGF-I.