INTERACTIONS OF TRANSFORMING-GROWTH-FACTOR-BETA AND ANGIOTENSIN-II INRENAL FIBROSIS

Overproduction of transforming growth factor-beta clearly underlies ti ssue fibrosis in numerous experimental and human diseases. Transformin g growth factor-beta's powerful fibrogenic action results from simulta neous stimulation of matrix protein synthesis, inhibition of matrix de gradation, and enhanced integrin expression that facilitates matrix as sembly. In animals, overexpression of transforming growth factor-beta by intravenous injection, transient gene transfer, or transgene insert ion has shown that the kidney is highly susceptible to rapid fibrosis. The same seems true in human disease, where excessive transforming gr owth factor-beta has been demonstrated in glomerulonephritis, diabetic nephropathy, and hypertensive glomerular injury. A possible explanati on for the kidney's particular susceptibility to fibrosis may be the r ecent discovery of biologically complex interactions between the renin -angiotensin system and transforming growth factor-beta. Alterations i n glomerular hemodynamics can activate both the renin-angiotensin syst em and transforming growth factor-beta. Components of the renin-angote nsin system act to further stimulate production of transforming growth factor-beta and plasminogen activator inhibitor leading to rapid matr ix accumulation. In volume depletion, transforming growth factor-beta is released from juxtaglomerular cells and may act synergistically wit h angiotensin II to accentuate vasoconstriction and acute renal failur e. Interaction of the renin-angiotensin system and transforming growth factor-beta has important clinical implications. The protective effec t of inhibition of the renin-angiotensin system in experimental and hu man kidney diseases correlates closely with the suppression of transfo rming growth factor-beta production. This suggests that transforming g rowth factor-beta, in addition to blood pressure, should be a therapeu tic target. Higher doses or different combinations of drugs that block the renin-angiotensin system or entirely new drug strategies may be n eeded to achieve a greater antifibrotic effect.