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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 2015 ; 308 (6): F594-601 Nephropedia Template TP
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An angiotensin-(1?7) peptidase in the kidney cortex, proximal tubules, and human HK-2 epithelial cells that is distinct from insulin-degrading enzyme #MMPMID25568136
Wilson BA; Cruz-Diaz N; Marshall AC; Pirro NT; Su Y; Gwathmey TM; Rose JC; Chappell MC
Am J Physiol Renal Physiol 2015[Mar]; 308 (6): F594-601 PMID25568136show ga
Angiotensin 1?7 [ANG-(1?7)] is expressed within the kidney and exhibits renoprotective actions that antagonize the inflammatory, fibrotic, and pro-oxidant effects of ANG II. We previously identified an peptidase that preferentially metabolized ANG-(1?7) to ANG-(1?4) in the brain medulla and cerebrospinal fluid (CSF) of sheep (Marshall AC, Pirro NT, Rose JC, Diz DI, Chappell MC. J Neurochem 130: 313?323, 2014); thus the present study established the expression of the peptidase in the kidney. Utilizing a sensitive HPLC-based approach, we demonstrate a peptidase activity that hydrolyzed ANG-(1?7) to ANG-(1?4) in the sheep cortex, isolated tubules, and human HK-2 renal epithelial cells. The peptidase was markedly sensitive to the metallopeptidase inhibitor JMV-390; human HK-2 cells expressed subnanomolar sensitivity (IC50 = 0.5 nM) and the highest specific activity (123 ± 5 fmol·min?1·mg?1) compared with the tubules (96 ± 12 fmol·min?1·mg?1) and cortex (107 ± 9 fmol·min?1·mg?1). The peptidase was purified 41-fold from HK-2 cells; the activity was sensitive to JMV-390, the chelator o-phenanthroline, and the mercury-containing compound p-chloromercuribenzoic acid (PCMB), but not to selective inhibitors against neprilysin, neurolysin and thimet oligopeptidase. Both ANG-(1?7) and its endogenous analog [Ala1]-ANG-(1?7) (alamandine) were preferentially hydrolyzed by the peptidase compared with ANG II, [Asp1]-ANG II, ANG I, and ANG-(1?12). Although the ANG-(1?7) peptidase and insulin-degrading enzyme (IDE) share similar inhibitor characteristics of a metallothiolendopeptidase, we demonstrate marked differences in substrate specificity, which suggest these peptidases are distinct. We conclude that an ANG-(1?7) peptidase is expressed within the renal proximal tubule and may play a potential role in the renal renin-angiotensin system to regulate ANG-(1?7) tone.