Isoproterenol induces mitogenesis in MCT and LLC-PK1 tubular cells

This study assessed the effects of exogenous isoproterenol on the proliferation of the proximal tubular cell lines MCT and LLC-PK1. Both cell lines express beta-adrenergic receptors as demonstrated by Scatchard analysis of binding data, receptor-cross linking studies, and mRNA expression for beta 2-adrenergic receptors. Isoproterenol (10(-7) M) for 15 min stimulated the formation of intracellular cAMP in MCT cells (controls, 8.0 +/- 0.7; isoproterenol, 12.6 +/- 0.89 fmol of cAMP/microgram of protein; P < 0.01). This effect was blocked by the beta-receptor antagonist propranolol (10(-6) M). Isoproterenol, in a dose-dependent manner, also induced proliferation in MCT and LLC-PK1 cells, as measured by [3H]thymidine incorporation and direct cell counts. Time-course experiments demonstrated maximal mitogenesis 48 h after a single dose of 10(-7) M isoproterenol. This mitogenic effect was mimicked by a stable cAMP analog or cholera toxin, but not by a cGMP analog, indicating that the isoproterenol-mediated growth effects are likely caused by cAMP. These results provide evidence that isoproterenol is a mitogenic growth factor for cultured proximal tubular cells. These findings may be important in the growth mechanisms involved in the proliferative remodeling of injured tubules after acute renal failure.