TY - JOUR
T1 - L-NIL prevents the ischemia and reperfusion injury involving TLR-4, GST, clusterin, and NFAT-5 in mice
AU - Pasten, Consuelo
AU - Alvarado, Cristóbal
AU - Rocco, Jocelyn
AU - Contreras, Luis
AU - Aracena, Paula
AU - Liberona, Jéssica
AU - Suazo, Cristian
AU - Michea, Luis
AU - Irarrázabal, Carlos E.
N1 - Funding Information:
Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)-1151157 supported this research. J. Liberona is holder of a Comisión Nacional de Investigación Científica y Tecnológica (CONICYT)-21150304 scholarship.
Publisher Copyright:
Copyright © 2019 the American Physiological Society.
PY - 2019/4
Y1 - 2019/4
N2 - —On renal ischemia-reperfusion (I/R) injury, recruitment of neutrophils during the inflammatory process promotes local generation of oxygen and nitrogen reactive species, which, in turn, are likely to exacerbate tissue damage. The mechanism by which inducible nitric oxide synthase (iNOS) is involved in I/R has not been elucidated. In this work, the selective iNOS inhibitor L-N6-(1-iminoethyl)lysine (L-NIL) and the NOS substrate L-arginine were employed to understand the role of NOS activity on the expression of particular target genes and the oxidative stress elicited after a 30-min of bilateral renal ischemia, followed by 48-h reperfusion in Balb/c mice. The main findings of the present study were that pharmacological inhibition of iNOS with L-NIL during an I/R challenge of mice kidney decreased renal injury, prevented tissue loss of integrity, and improved renal function. Several novel findings regarding the molecular mechanism by which iNOS inhibition led to these protective effects are as follows: 1) a prevention of the I/R-related increase in expression of Toll-like receptor 4 (TLR-4), and its downstream target, IL-1α; 2) reduced oxidative stress following the I/R challenge; noteworthy, this study shows the first evidence of glutathione S-transferase (GST) inactivation following kidney I/R, a phenomenon fully prevented by iNOS inhibition; 3) increased expression of clusterin, a survival autophagy component; and 4) increased expression of nuclear factor of activated T cells 5 (NFAT-5) and its target gene aquaporin-1. In conclusion, prevention of renal damage following I/R by the pharmacological inhibition of iNOS with L-NIL was associated with the inactivation of proinflammatory pathway triggered by TLR-4, oxidative stress, renoprotection (autophagy inac-tivation), and NFAT-5 signaling pathway.
AB - —On renal ischemia-reperfusion (I/R) injury, recruitment of neutrophils during the inflammatory process promotes local generation of oxygen and nitrogen reactive species, which, in turn, are likely to exacerbate tissue damage. The mechanism by which inducible nitric oxide synthase (iNOS) is involved in I/R has not been elucidated. In this work, the selective iNOS inhibitor L-N6-(1-iminoethyl)lysine (L-NIL) and the NOS substrate L-arginine were employed to understand the role of NOS activity on the expression of particular target genes and the oxidative stress elicited after a 30-min of bilateral renal ischemia, followed by 48-h reperfusion in Balb/c mice. The main findings of the present study were that pharmacological inhibition of iNOS with L-NIL during an I/R challenge of mice kidney decreased renal injury, prevented tissue loss of integrity, and improved renal function. Several novel findings regarding the molecular mechanism by which iNOS inhibition led to these protective effects are as follows: 1) a prevention of the I/R-related increase in expression of Toll-like receptor 4 (TLR-4), and its downstream target, IL-1α; 2) reduced oxidative stress following the I/R challenge; noteworthy, this study shows the first evidence of glutathione S-transferase (GST) inactivation following kidney I/R, a phenomenon fully prevented by iNOS inhibition; 3) increased expression of clusterin, a survival autophagy component; and 4) increased expression of nuclear factor of activated T cells 5 (NFAT-5) and its target gene aquaporin-1. In conclusion, prevention of renal damage following I/R by the pharmacological inhibition of iNOS with L-NIL was associated with the inactivation of proinflammatory pathway triggered by TLR-4, oxidative stress, renoprotection (autophagy inac-tivation), and NFAT-5 signaling pathway.
KW - Clusterin
KW - GST
KW - Ischemia-reperfusion
KW - L-NIL
KW - TLR-4
KW - Clusterin
KW - GST
KW - Ischemia-reperfusion
KW - L-NIL
KW - TLR-4
UR - http://www.scopus.com/inward/record.url?scp=85063603634&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00398.2018
DO - 10.1152/ajprenal.00398.2018
M3 - Article
C2 - 30516425
AN - SCOPUS:85063603634
SN - 1931-857X
VL - 316
SP - F624-F634
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 4
ER -