Nitro-oleic acid protects the mouse kidney from ischemia and reperfusion injury

Abstract

Nitroalkene derivatives of linoleic acid (nitrolinoleic acid; LNO2) and nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties. The present study was undertaken to evaluate the therapeutic potential of OA-NO2 in a mouse model of renal ischemia-reperfusion (I/R) injury. B6129SF2/J mice were subjected to bilateral renal ischemia for 30 min, followed by 24 h of reperfusion. Fifty minutes after ischemia, mice received intraperitoneal (ip) injections of OA-NO2 (500 microg/kg; I/R OA-NO2), vehicle for OA-NO2 (i.e., 0.8 ml/kg ethanol; I/R veh), or oleic acid (500 microg/kg; I/R OA) every 6 h during the 24-h recovery period. A sham-operated group was not subjected to ischemia and received 0.8 ml/kg ethanol ip every 6 h during the 24-h recovery period (sham veh). While plasma urea and creatinine were elevated (P<0.05) in I/R veh vs. sham veh mice, the severity was less (P<0.05) in I/R OA-NO2 animals. Indices of histological damage, polymorphonucleocyte infiltration, together with expression of intracellular adhesion molecule-1, interleukin-1beta, and tumor necrosis factor-alpha, p47(phox), and gp91(phox) were greater in I/R veh vs. sham veh mice, but were attenuated (P<0.05) in I/R OA-NO2 animals. Because indices of renal dysfunction were similar between I/R veh and I/R OA mice (P>0.05), but less (P<0.05) in I/R OA-NO2 animals compared with both groups, protection from bilateral renal ischemia is afforded by the nitrated but not free form of oleic acid. Together, delayed administration of nitrated fatty acid OA-NO2 attenuates renal I/R injury in the mouse likely via inhibition of the inflammatory response.

Conjugated Linoleic Acid Is a Preferential Substrate for Fatty Acid Nitration

“…The consideration of the endogenous generation, metabolism, and reactions of electrophilic NO 2 -FA is of relevance because these species potently limit inflammation via multiple mechanisms, including PPAR␥ activation, the inhibition of expression of pro-inflammatory NF-B-regulated genes, and up-regulation of HO-1 and other phase 2 genes regulated by Keap1/Nrf2. Thus, in murine models of metabolic and inflammatory injury, fatty acid nitroalkene administration at nanomolar concentrations prevents restenosis after vessel injury (49), limits weight gain and loss of insulin sensitivity in murine models of metabolic syndrome (14), protects against ischemia-reperfusion injury (17,47,50), reduces plaque formation in a rodent model of atherosclerosis (51), and inhibits the onset of chemically induced inflammatory bowel disease (52).…”

Characterization and quantification of endogenous fatty acid nitroalkene metabolites in human urine

“…Critical pro-infl ammatory enzymatic activities are also inhibited by fatty acid nitroalkenes, including xanthine oxidoreductase and cyclooxygenase-2 ( 52,53 ). These actions result in antiinfl ammatory responses in diverse animal models of disease including limiting restenosis after vessel injury ( 54 ), attenuation of weight gain and loss of insulin sensitivity in murine models of metabolic syndrome ( 6, 55 ), inhibition of sepsis-induced renal failure ( 56 ), prevention of ischemia-reperfusion injury ( 31,32,57 ), reduction of plaque formation in a murine ApoE Ϫ / Ϫ atherosclerosis model, and the reduction of chemically-induced infl ammatory bowel disease ( 47 ). Notably, all of these clinically-relevant responses are induced by steady state plasma concentrations of nitro-fatty acids ranging from 10 to 25 nM, well within the range of NO 2 -CLA concentrations measured in human urine (9.2 ± 4.3 nM).…”

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

“…The electrophilic properties of NO 2 -FA induce anti-inflammatory and cytoprotective actions via reversible posttranslational modification of transcriptional regulatory proteins, such as NF-kB, Keap1/ Nrf2, and PPAR-, and enzymes such as xanthine oxidoreductase and sEH (6)(7)(8)(36)(37)(38). Beneficial metabolic and anti-inflammatory effects of NO 2 -FAs have been shown in animal models of fibrosis, atherosclerosis, renal and cardiac ischemia reperfusion, restenosis, and diabetes (12,(39)(40)(41)(42)(43)(44). in nitro-alkane metabolites could reflect their cellular reuptake and esterification into complex lipids.…”