ENDOTHELIAL-CELL INJURY INITIATES GLOMERULAR SCLEROSIS IN THE RAT REMNANT KIDNEY

The development of progressive glomerulosclerosis in the renal ablatio n model has been ascribed to a number of humoral and hemodynamic event s, including the peptide growth factor, transforming growth factor-bet a 1 (TGF-beta 1), An important role has also been attributed to angiot ensin II (AII), which, in addition to its hemodynamic effects, can sti mulate transcription of TGF-beta 1. We postulated that increased glome rular production of AII, resulting from enhanced intrinsic angiotensin ogen expression, stimulates local TGF-beta 1 synthesis, activating glo merular matrix protein synthesis, and leads to sclerosis, Using in sit u reverse transcription, the glomerular cell sites of alpha-1 (IV) col lagen, fibronectin, laminin B1, angiotensinogen, and TGF-beta 1 mRNA s ynthesis were determined at sequential periods following renal ablatio n, The early hypertrophic phase was associated with global, but transi ent, increases in the mRNA for alpha-1 (IV) collagen, No changes were noted for fibronectin, TGF-beta 1, and angiotensinogen mRNAs, At 24 d after ablation, at which time sclerosis is not evident, endothelial ce lls, particularly in the dilated capillaries at the vascular pole, exp ressed angiotensinogen and TGF-beta 1 mRNAs, as well as fibronectin an d laminin B1 RNA transcripts, By 74 d after ablation angiotensinogen a nd TGF-beta 1 mRNAs were widely distributed among endothelial and mesa ngial cells, and were particularly prominent in regions of evolving sc lerosis, These same regions were also notable for enhanced expression of matrix protein mRNAs, particularly fibronectin, All receptor blocka de inhibited angiotensinogen, TGF-beta 1, fibronectin, and laminin B1 mRNA expression by the endothelium, We conclude that, as a result of h emodynamic changes, injured or activated endothelium synthesizes angio tensinogen, triggering a cascade of TGF-beta 1 and matrix protein gene expression with resultant development of the segmental glomerular scl erotic lesion.