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2015 ; 10
(3
): e0120728
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Abrogation of plasminogen activator inhibitor-1-vitronectin interaction
ameliorates acute kidney injury in murine endotoxemia
#MMPMID25799354
Gupta KK
; Donahue DL
; Sandoval-Cooper MJ
; Castellino FJ
; Ploplis VA
PLoS One
2015[]; 10
(3
): e0120728
PMID25799354
show ga
Sepsis-induced acute kidney injury (AKI) contributes to the high mortality and
morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly
understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1)
and vitronectin (Vn) are involved in AKI. However, the functional cooperation
between PAI-1 and Vn in septic AKI has not been completely elucidated. To address
this issue, mice were utilized lacking either PAI-1 (PAI-1-/-) or expressing a
PAI-1-mutant (PAI-1R101A/Q123K) in which the interaction between PAI-1 and Vn is
abrogated, while other functions of PAI-1 are retained. It was found that both
PAI-1-/- and PAI-1R101A/Q123K mice are associated with decreased renal
dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type
(WT) mice after LPS challenge. Also, PAI-1-/- mice showed attenuated fibrin
deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction
was found to be associated with an increase in activated Protein C (aPC) in
plasma. These results demonstrate that PAI-1, through its interaction with Vn,
exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the
PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for
the treatment of septic AKI by not only altering the fibrinolytic capacity but
also regulating PC activity.