DIFFERENTIAL EXPRESSION OF GLOMERULAR EXTRACELLULAR-MATRIX AND GROWTH-FACTOR MESSENGER-RNA IN RAPID AND SLOWLY PROGRESSIVE GLOMERULOSCLEROSIS - STUDIES IN MICE TRANSGENIC FOR NATIVE OR MUTATED GROWTH-HORMONE

We found that mice transgenic for native bovine growth hormone (bGH) g ene had increased body size and rapidly progressive glomerulosclerosis , whereas mice transgenic for a mutated bGH gene (bGH-m11) had near no rmal body size and slowly progressive glomerulosclerosis. The aim of t his study was to determine whether rapidly and slowly progressive glom erulosclerosis had distinct glomerular extracellular matrix (ECM) and growth factor mRNA levels. ECM and growth factors were quantitated by competitive reverse transcriptase-PCR in microdissected glomeruli from bGH, bGH-m11, and nontransgenic littermate control mice. In rapid pro gressors (bGH mice) at 2 to 3 months, the levels of mRNA-coding for so me glomerular ECM and growth factors were increased (alpha 1(IV) colla gen, 7.3-fold; laminin B1, 3.9-fold; tenascin, 8-fold; and tumor growt h factor (TGF)-beta 1, 3.4-fold). These levels underwent a further 2.3 -fold increase at 6 to 9 months. Platelet-derived growth factor (PDGF) -B mRNA was high at 2 to 3 months (7.4-fold) and 6 to 9 months (9.5-fo ld) and was associated with an increased [H-3]-thymidine-labelling ind ex and glomerular cell number. In slow progressors (bGH-m11 mice), the mRNA levels at 2 to 3 months were approximately one half that of rapi d progressors (alpha 1(IV) collagen, 3.4-fold; laminin B1 1.9-fold; te nascin, 3-fold; TGF-beta 1, 2.2-fold). PDGF-B levels were normal. At 6 to 9 months, alpha 1(IV) collagen, TGF-beta 1, and PDGF-B mRNA levels doubled, whereas tenascin and laminin B1 levels remained stable. At 1 2 to 18 months, the alpha 1(IV) collagen, TGF-beta 1, and tenascin lev els increased by nearly another 50%. The labelling index and PDGF leve ls were not increased at any time. The levels of expression of several glomerular ECM mRNA and growth factors of rapid progressors at 2 to 3 months of age was nearly double that of slow progressors, nearly doub ling again by 6 to 9 months. In slow progressors, alpha 1(IV)collagen and TGF-beta 1 mRNA levels continued to increase at a slow rate, but t enascin and laminin mRNA levels were only further increased at 12 to 1 8 months. Thus, the initial levels of these mRNA and their rate of cha nge correlated with the severity of glomerulosclerosis.