Decreased endogenous levels of Ac-SDKP promote organ fibrosis.

There is convincing evidence that chronic treatment with N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a peptide normally found in tissues and biological fluids, reduces collagen deposition in the heart and kidneys of hypertensive rats and rats with myocardial infarction. However, it is not known whether endogenous Ac-SDKP at basal concentrations has any physiological function related to collagen deposition. Prolyl oligopeptidase is responsible for release of Ac-SDKP from its precursor thymosin-beta(4). When we treated rats with a specific oral rolyl oligopeptidase inhibitor, Ac-SDKP decreased significantly in the plasma, heart, and kidney. In the present study, we tested the hypothesis that endogenous Ac-SDKP at basal levels plays a physiological role, antagonizing and/or preventing excessive collagen deposition. We studied whether chronic blockade of Ac-SDKP promotes collagen accumulation and/or accelerates this process in the presence of a profibrotic stimulus such as angiotensin II. We found that decreased basal levels of Ac-SDKP increased cardiac and renal perivascular fibrosis and promoted glomerulosclerosis. Moreover, in the presence of angiotensin II decreasing basal levels of Ac-SDKP accelerated interstitial cardiac fibrosis attributable to an increase in cells that produce collagen. We concluded that Ac-SDKP participates in the regulation of collagen content under normal conditions. We believe this is the first study showing that this peptide plays a physiological role at basal concentrations, preventing organ collagen accumulation.