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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
PMID25568136
show 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 [Ala(1)]-ANG-(1-7) (alamandine) were preferentially hydrolyzed
by the peptidase compared with ANG II, [Asp(1)]-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.
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