ANGIOTENSIN-II INDUCES HYPERTROPHY AND HYPERPLASIA IN ADULT HUMAN MESANGIAL CELLS

Several experimental studies point to a potential role of angiotensin II (Ang II) in the progression of glomerulosclerosis even in the absen ce of glomerular hypertension. We tested the hypothesis that Ang II ac ts as a growth factor For adult human mesangial cells (AHMC). AHMC wer e isolated from noninvolved parts of tumor nephrectomy specimens and g rown in RPMI medium with the addition of fetal calf serum (FCS). All s tudies were performed with growth-arrested cells. Proliferation studie s were done in serum-fret standard growth medium (SF) with the additio n of either various concentrations of insulin, plasma-derived serum, o r FCS. Ang II (10(-10) to 10(-6) M) dose dependently increased the H-3 -thymidine uptake of AHMC up to 57 +/- 13% over solvent controls (p < 0.01). In parallel, the DNA content was 36 +/- 10% higher (p < 0.05) t han in solvent controls after 2 days of culture. The cell numbers were higher up to 47 +/- 8% in Ang II (10(-6) M) stimulated cultures after 4 days of incubation (p < 0.01). The effect of Ang II was specific, s ince it was almost completely obliterated by the AT(1) receptor antago nist DuP753. The effect of Ang II was particularly marked when culture s were incubated with SF plus high concentrations (1.7 x 10(-6) M) of insulin or SF plus 10% plasma-derived serum. In contrast, the effect w as not significant when cultures were incubated with SF plus 10% FCS. Ang II, when added to platelet-derived growth factor at various concen trations, did not further increase the proliferation. The effect on pr otein synthesis was assessed in growth-arrested AHMC by H-3-methionine uptake and protein/DNA ratio in cell lysates. Ang II(10(-10) to 10(-6 ) M) dose dependently increased the H-3-methionine uptake of AHMC up t o 47 +/- 10% over solvent controls (p <0.01). In parallel Ang II (10(- 8) M) increased the protein/DNA ratio by 24 +/- 6% after 48 h of incub ation. DuP753 obliterated the stimulatory effect of Ang II. Ang II (10 (-6) M) also increased the mRNA of the immediate-early growth-related gene Egr-1. We conclude that Ang II induces hypertrophy and proliferat ion in adult human mesangial cells. This result is of interest with re spect to a potential role of Ang II in the pathogenesis of glomerulosc lerosis in humans.