¹Departments of Medicine and Physiology, University of Sydney, Sydney, New South Wales, Australia

Correspondence: Dr Carol A. Pollock, Department of Medicine, Level 3, Wallace Freeborn Professorial Block, Royal North Shore Hospital, Pacific Highway, St Leonards 2065, Australia. E-mail: carpol@blackburn.med.su.oz.au

Received 3 September 1997; Revised 17 December 1997; Accepted 17 December 1997.

Abstract

TGF-₁dissociates human proximal tubule cell growth and Na⁺-H⁺ exchange activity. Stimulation of proximal tubule cell (PTC) growth in a variety of physiological and pathological renal conditions is preceded by increased renal production of transforming growth factor-₁ (TGF-₁) and by augmented tubular sodium transport via activated sodium hydrogen exchange (NHE). Since TGF-₁ has been shown to be an important paracrine and autocrine regulator of PTC growth, the hypothesis that TGF-₁ modulates basal and mitogen-stimulated PTC growth via an effect on NHE activity was examined. Confluent, quiescent, human PTC were incubated for 24 hours in serum-free media containing vehicle (control) or 1 ng/ml TGF-₁, in the presence or absence of 100 ng/ml insulin-like growth factor-1 (IGF-I). Under basal conditions, TGF-₁ inhibited thymidine incorporation (73.5 7.3% of control, P < 0.05), but exerted no effect on cellular protein content (97.4 10.7% of control), an index of hypertrophy. There was no significant alteration of NHE activity, measured as ethylisopropylamiloride (EIPA)-sensitive H⁺ efflux (2.72 0.50 vs. control 3.26 0.68 mmol/liter/min) or ²²Na⁺ influx (2.20 0.23 vs. control 2.19 0.19 nmol/mg protein/min). When co-incubated with IGF-I, TGF-₁ induced significant PTC hypertrophy (116.9 8.2% of control, P < 0.05), which was not seen with either agent alone. TGF-₁ counteracted the stimulatory effect of IGF-I on DNA synthesis (TGF-₁+IGF-I 103.0 7.3% vs. IGF-I alone 181.2 30.3% of control, P < 0.05), but did not affect IGF-I-stimulated EIPA-sensitive ²²Na⁺ influx (3.63 0.63 vs. IGF-I alone 3.67 0.50 nmol/mg protein/min, P = NS, both vs. control 2.19 0.19 nmol/mg protein/min, P < 0.05). Similar results were obtained when NHE activity was measured as EIPA-sensitive H⁺ efflux. Moreover, the kinetics of NHE activation by the combination of TGF-₁ and IGF-I (involving an increase in V_max) were identical to that previously found for PTC exposed to IGF-I alone. The study demonstrates that TGF-₁ elicits distinct PTC growth responses in the presence and absence of IGF-I, without modification of NHE activity. The combination 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-₁ and IGF-I.