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    L-NIL prevents the ischemia and reperfusion injury involving TRL4, GST, clusterin and NFAT5 in mice

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    Alvarado, Cristobal-L-NIL prevents.pdf (61.67Mb)
    Date
    2019-04
    Author
    Pasten, María
    Alvarado, Cristóbal
    Rocco, Jocelyn
    Contreras, Luis
    Aracena, Paula
    Liberona, Jéssica
    Suazo, Cristian
    Michea, Luis
    Irarrázabal, Carlos E.
    Publisher
    American journal of physiology. Renal physiology
    Description
    Artículo de investigación
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    Abstract
    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-1β; 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 inactivation), and NFAT-5 signaling pathway.
    URI
    http://repositoriodigital.ucsc.cl/handle/25022009/2067
    Ir a texto completo en URI:
    https://doi.org/10.1152/ajprenal.00398.2018
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