Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

Inhibitors of the renin-angiotensin-aldosterone system attenuate glomerulosclerosis and interstitial fibrosis. Although the mechanisms underlying their antifibrotic effects are complex, angiotensin II (Ang II) emerges as a major profibrogenic cytokine. Ang II modulates renal cell growth, extracellular matrix synthesis, and degradation by multiple fibrotic pathways. One of the main targets of Ang II in renal fibrosis is TGF beta. Many, but not all, of the stimulatory effects of Ang II on fibrogenesis depend on the induction of TGF beta and its downstream mediators of matrix accumulation, inflammation, and apoptosis. However because of the difficulty in targeting TGF beta, connective tissue growth factor beta (CTGF), a downstream mediator of TGF beta, has become a more promising antifibrotic target. Ang II can directly induce expression of renal CTGF and mediate epithelial-mesenchymal transition. Other profibrotic factors stimulated by Ang II include endothelin-1, plasminogen activator inhibitor-1, matrix metalloproteinase (MMP)-2, and a tissue inhibitor of metalloproteinase-2. Finally, connections among Ang II, hypoxia, and the induction, of hypoxia-inducible factor-1 alpha contribute to fibrogenesis. A better understanding of the multiple morphogenic effects of Ang II may be necessary to develop better strategies to halt the progression of renal disease.