COMPARATIVE-STUDY OF ACE-INHIBITORS AND ANGIOTENSIN-II RECEPTOR ANTAGONISTS IN INTERSTITIAL SCARRING

Many of the pathophysiologic events associated with kidney disease are driven by angiotensin II. Irrespective of the etiology, many kidney d iseases lead to tubulointerstitial inflammation, fibrosis and loss of renal function. Contributors to the process of tubulointerstitial fibr osis include monocyte/macrophage infiltration, the synthesis of profib rotic cytokines such as transforming growth factor beta 1 (TGF-beta 1) , interstitial myofibroblast proliferation, and clusterin expression. These processes are ameliorated by angiotensin converting enzyme (ACE) inhibition. Blockade of the angiotensin II receptor (AT-1) impaired f ibroblast proliferation, consequent differentiation into myofibroblast s, and the synthesis of TGF-beta 1, but did not prevent monocyte infil tration. AT-2 receptor blockade did not attenuate monocyte/macrophage infiltration, TGF-beta 1 synthesis or fibroblast proliferation but pre vented the differentiation of fibroblasts into myofibroblasts and bloc ked clusterin expression. The nuclear factor-kappa B (NF-kappa B) fami ly of transcription factors regulates genes involved in inflammation, proliferation and differentiation. ACE inhibition, AT-1 and AT-2 recep tor blockade each differentially attenuated NF-kappa B isotype activat ion. The changes in NF-kappa B isotype may account for the variation s een in the pharmacologic effect of angiotensin II formation or action on the fibrotic process. When considering therapeutic options to preve nt renal disease progression, one must be aware of the impact of trans cription factors on the injured kidney and the consequent changes in c ell infiltration, proliferation and differentiation.