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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Renal+Physiol 2016 ; 310 (10): F1026-34 Nephropedia Template TP
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The anti-inflammatory peptide Ac-SDKP is released from thymosin-?4 by renal meprin-? and prolyl oligopeptidase #MMPMID26962108
Am J Physiol Renal Physiol 2016[May]; 310 (10): F1026-34 PMID26962108show ga
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin-?4 (T?4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and T?4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, T?4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide(s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-? metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, T?4 is hydrolyzed by meprin-?. In vitro, we found that the incubation of T?4 with both meprin-? and POP released Ac-SDKP, whereas no Ac-SDKP was released when T?4 was incubated with either meprin-? or POP alone. Incubation of T?4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-? inhibitor actinonin. In addition, kidneys from meprin-? knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-? KO mice failed to release Ac-SDKP from T?4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 ± 0.2 nmol/l; captopril, 15.1 ± 0.7 nmol/l; captopril + actinonin, 6.1 ± 0.3 nmol/l; P < 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from T?4 is mediated by successive hydrolysis involving meprin-? and POP.