Local induction of angiotensin-converting enzyme in the kidney as a mechanism of progressive renal diseases

Abstract

Angiotensin Converting Enzyme (ACE) or Kininase II has a pivotal role determining the local activity of the renin angiotensin and kallikrein kinin systems. Angiotensin II (Ang II), a main hormone of the renin system, has a well established participation as a renal injury agent in models of renal disease with tubulointerstitial fibrosis. Although, since its discovery, ACE has been known to convert Ang I to Ang II, and to inactivate bradykinin (BK), only recently has been emerged evidence for a role of BK with renal protective and antifibrotic effects opposing Ang II. Pertinent to the tubulointerstitial injury, where infiltration and proliferation of macrophages and fibroblast occur, ACE also regulates the levels of the natural hemoregulatory peptide, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Owing the importance of tissue ACE, its distribution was studied in several models of renal injury. The results showed increased ACE in proximal tubules and ACE induction in the cell infiltrated tubulointerstitium (macrophages and myofibroblasts) of injured kidneys from hypokalemic, Goldblatt hypertensive, Ang II and phenylefrine infused rats, and in both human diabetic and membranous nephropathies. ACE, in addition to Ang II generation, may play a pathogenic role through the hydrolysis of BK and Ac-SDKP. Thus, local increase in ACE can be a novel mechanism involved in tubulointerstitial renal injury, providing, from an anatomical ground, a pathological basis for the putative deleterious effect of ACE in the diseased kidneys, and the beneficial effect of ACE inhibition.