(Hypertension. 1998;31:181.)
© 1998 American Heart Association, Inc.
Workshop on Vascular Biology & Hypertension: From Molecules to Humans |
Interactions of Transforming Growth Factor-ß and Angiotensin II in Renal Fibrosis
From the Division of Nephrology and Hypertension, Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah.
Correspondence to Wayne A. Border, MD, Division of Nephrology and Hypertension, Department of Medicine, University of Utah Health Sciences Center, 50 North Medical Drive, Salt Lake City, UT 84132. E-mail wborder{at}msscc.med.utah.edu
Overproduction of transforming growth factor-ß clearly underlies tissue fibrosis in numerous experimental and human diseases. Transforming growth factor-ß’s powerful fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation, and enhanced integrin expression that facilitates matrix assembly. In animals, overexpression of transforming growth factor-ß by intravenous injection, transient gene transfer, or transgene insertion has shown that the kidney is highly susceptible to rapid fibrosis. The same seems true in human disease, where excessive transforming growth factor-ß has been demonstrated in glomerulonephritis, diabetic nephropathy, and hypertensive glomerular injury. A possible explanation for the kidney’s particular susceptibility to fibrosis may be the recent discovery of biologically complex interactions between the renin-angiotensin system and transforming growth factor-ß. Alterations in glomerular hemodynamics can activate both the renin-angiotensin system and transforming growth factor-ß. Components of the renin-angiotensin system act to further stimulate production of transforming growth factor-ß and plasminogen activator inhibitor leading to rapid matrix accumulation. In volume depletion, transforming growth factor-ß is released from juxtaglomerular cells and may act synergistically with angiotensin II to accentuate vasoconstriction and acute renal failure. Interaction of the renin-angiotensin system and transforming growth factor-ß has important clinical implications. The protective effect of inhibition of the renin-angiotensin system in experimental and human kidney diseases correlates closely with the suppression of transforming growth factor-ß production. This suggests that transforming growth factor-ß, in addition to blood pressure, should be a therapeutic target. Higher doses or different combinations of drugs that block the renin-angiotensin system or entirely new drug strategies may be needed to achieve a greater antifibrotic effect.
Key Words: transforming growth factor-ß • angiotensin II • kidney • fibrosis
Abbreviations: Ang II = angiotensin II • ACE = angiotensin-converting enzyme • AT1 = angiotensin II type 1 • ATS = anti-thymocyte serum • JGA = juxtaglomerular apparatus • PAI = plasminogen activator inhibitor • RAS = renin-angiotensin system • TGF-ß = transforming growth factor-ß
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