Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors

In recent decades there has been a tremendous increase in the therapeutic options available for the inhibition of the renin-angiotensin system (RAS). Historically, angiotensin-converting enzyme inhibitors (ACE-I) were the first class of RAS inhibitors identified. The first ACE-I, captopril, was discovered by a scientist at Squibb, a US pharmaceutical company, in 1975 [1]. Captopril was based on the peptide sequence of bradykinin-potentiating factor, which inhibited the conversion of angiotensin I to angiotensin II when perfused into pulmonary circulation [2].Approximately 15 years ago, a second class of RAS inhibitors was introduced into the market, the angiotensin II receptor blockers (ARBs) [3]. Very recently, a novel class of RAS inhibitor, including aliskiren [4], which directly inhibits renin has been put into clinical use. Most of the literature support the beneficial effects of this novel class of RAS inhibitors as antihypertensive drugs [5,6]. Interestingly, the use of these drugs is not limited to antihypertensive disorders. The clinical use of RAS inhibitors has emerged as beneficial for the prevention of diabetes [7,8], fibrotic kidney disease [9], heart disease [10], aging [11] and Alzheimer's disease [12].There is no doubt that RAS inhibitors are beneficial drugs; however, the differences between each of these classes of inhibitors are not yet clear. After a brief introduction to the RAS, we analyze the potential differences between ACE-I and ARBs as antifibrotic drugs. Emphasis is placed on the ACE inhibitors and the antifibrotic peptide AcSDKP.Renin, an aspartyl protease, was discovered by Robert Tigerstedt at the Karolinska Institute in 1898 [13]. The majority of renin in the body is found in the juxtaglomerular cells of the kidney. Additionally, renin has been found in many other tissues but without clear mechanistic evidence of its function in these locations [14]. Renin cleaves angiotensinogen, which results in the production of the decapeptide an