| First Author | Kumar N | Year | 2016 |
| Journal | Am J Physiol Renal Physiol | Volume | 310 |
| Issue | 10 | Pages | F1026-34 |
| PubMed ID | 26962108 | Mgi Jnum | J:280671 |
| Mgi Id | MGI:6368978 | Doi | 10.1152/ajprenal.00562.2015 |
| Citation | Kumar N, et al. (2016) The anti-inflammatory peptide Ac-SDKP is released from thymosin-beta4 by renal meprin-alpha and prolyl oligopeptidase. Am J Physiol Renal Physiol 310(10):F1026-34 |
| abstractText | 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-beta4 (Tbeta4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and Tbeta4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, Tbeta4 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-alpha metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, Tbeta4 is hydrolyzed by meprin-alpha. In vitro, we found that the incubation of Tbeta4 with both meprin-alpha and POP released Ac-SDKP, whereas no Ac-SDKP was released when Tbeta4 was incubated with either meprin-alpha or POP alone. Incubation of Tbeta4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-alpha inhibitor actinonin. In addition, kidneys from meprin-alpha knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-alpha KO mice failed to release Ac-SDKP from Tbeta4. 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 Tbeta4 is mediated by successive hydrolysis involving meprin-alpha and POP. |
