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Protection of nitro-fatty acid against kidney diseases.

ABSTRACT: Nitrated derivatives of unsaturated fatty acids are endogenously formed under oxidative and nitrative stress condition and are defined as electrophilic fatty acids containing a nitro group to a carbon-carbon double bond. Among the most studied nitro derivatives of unsaturated fatty acids are nitro-oleic acid (OA-NO2) and nitro-linoleic acid (LNO2). These products exhibit novel protective actions in a variety of rodent disease models. Diverse signaling events are responsible for effects of nitrated fatty acid, including activating peroxisome proliferator-activated receptor-dependent gene expression, suppressing NF-?B-induced inflammation, inhibiting oxidative stress, and increasing both endothelial nitric oxide synthase- and Nrf2-dependent gene regulation. Nitrated fatty acids have been emerging not only as a unique class of signaling molecules produced endogenously and but also as multipotent modulators of cell signaling pathways in cardiovascular and renal diseases. In this review, we discuss biochemical properties of nitrated fatty acid and its signaling pathways in the modulation of cellular events. A major focus is to review recent knowledge of nitrated fatty acid on the treatment of kidney diseases and its therapeutic potential for inflammation and metabolic disorders, with special emphasis on acute kidney injury and diabetic kidney disease.

SUBMITTER: Wang W

PROVIDER: S-EPMC4835926 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Protection of nitro-fatty acid against kidney diseases.

Wang Weidong W Li Chunling C Yang Tianxin T

American journal of physiology. Renal physiology 20151230 8

Nitrated derivatives of unsaturated fatty acids are endogenously formed under oxidative and nitrative stress condition and are defined as electrophilic fatty acids containing a nitro group to a carbon-carbon double bond. Among the most studied nitro derivatives of unsaturated fatty acids are nitro-oleic acid (OA-NO<sub>2</sub>) and nitro-linoleic acid (LNO<sub>2</sub>). These products exhibit novel protective actions in a variety of rodent disease models. Diverse signaling events are responsible ...[more]

PMID: 26719362

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Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.

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Protection of nitro-fatty acid against kidney diseases.

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Protection of nitro-fatty acid against kidney diseases.

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