Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring

Abstract

Many of the pathophysiologic events associated with kidney disease are driven by angiotensin II. Irrespective of the etiology, many kidney diseases lead to tubulointerstitial inflammation, fibrosis and loss of renal function. Contributors to the process of tubulointerstitial fibrosis include monocyte/macrophage infiltration, the synthesis of profibrotic 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 fibroblast proliferation, consequent differentiation into myofibroblasts, and the synthesis of TGF-beta 1, but did not prevent monocyte infiltration. TGF-beta 1 synthesis or fibroblast proliferation but prevented the differentiation of fibroblasts into myofibroblasts and blocked clusterin expression. The nuclear factor-kappa B (NF-kappa B) family of transcription factors regulates genes involved in inflammation, proliferation and differentiation. ACE inhibition, AT-1 and AT-2 receptor blockade each differentially attenuated NF-kappa B isotype activation. The changes in NF-kappa B isotype may account for the variation seen in the pharmacologic effect of angiotensin II formation or action on the fibrotic process. When considering therapeutic options to prevent renal disease progression, one must be aware of the impact of transcription factors on the injured kidney and the consequent changes in cell infiltration, proliferation and differentiation.