L-NIL prevents the ischemia and reperfusion injury involving TLR-4, GST, clusterin, and NFAT-5 in mice

Consuelo Pasten, Cristóbal Alvarado, Jocelyn Rocco, Luis Contreras, Paula Aracena, Jéssica Liberona, Cristian Suazo, Luis Michea, Carlos E. Irarrázabal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


—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.

Original languageEnglish
Pages (from-to)F624-F634
JournalAmerican Journal of Physiology - Renal Physiology
Issue number4
StatePublished - Apr 2019

Bibliographical note

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.


  • Clusterin
  • GST
  • Ischemia-reperfusion
  • L-NIL
  • TLR-4


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