An important aspect of cellular function during I/R is the modulation of metabolite transport across the plasma membrane, which may be involved in cell injury or repair mechanisms. The transport of small molecules across biological membranes is essential for maintaining cellular homeostasis and adaptation to environmental changes. It is believed that reactive oxygen species produced in reperfused cells and inflammatory responses are the key mediators of reperfusion injury ( 29).
However, reperfusion causes additional damage (reperfusion injury). If ischemia is transient and blood flow restored within a short time, most ischemic damage can be reversed. Third, severe mitochondrial damage occurs, including breakdown of membrane lipid, modification of electron transfer chain proteins, and most importantly, mitochondrial permeability transition ( 15).
Many of these proteins mediate degradation of cellular components (protein, nucleic acid, lipid) in necrosis and apoptosis. This has profound effects on cellular functions due to the activation of a wide range of proteins by Ca 2+, including proteases, endonucleases, phospholipases, protein kinases/phosphatases, and transcription factors.
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Second, cytosolic free Ca 2+ concentration increases because the activities of membrane-associated ATP-dependent Ca 2+ pumps are reduced, resulting in a net influx of Ca 2+ from extracellular space, mitochondria, and ER lumens. As a result, cells accumulate sodium and other solutes while losing potassium, causing the cell and cellular organelles (mitochondria and endoplasmic reticulum ) to swell due to water gained from osmotic balance. First, the activities of energy-dependent Na +/K +-ATPases are diminished. There are several important consequences of ATP depletion. As the cellular oxygen is depleted, mitochondrial oxidative phosphorylation and ATP production rates decrease. Ischemic tissue is deprived of oxygen and essential substrates for energy metabolism. Similar to other stress conditions, I/R causes dramatic changes in cell physiology and metabolism. Ischemia/reperfusion (I/R) is the major cause of tissue injury under many pathophysiological conditions such as stroke, myocardial infarction, and acute renal failure ( 1, 11). On the basis of these results, we propose that IRIP regulates the activity of a variety of transporters under normal and pathological conditions. We measured transport kinetics of OCT2-mediated uptake and demonstrated that IRIP overexpression significantly decreased V max but did not affect K m. Conversely, inhibition of IRIP expression by small interfering RNA or antisense RNA increased MPP + uptake. The activities of exogenous organic cation transporters (OCT2 and OCT3), organic anion transporter (OAT1), and monoamine transporters were also inhibited by IRIP. IRIP overexpression inhibited endogenous 1-methyl-4-phenylpyridinium (MPP +) uptake activity in HeLa cells. A possible role of IRIP in regulating transporter activity was subsequently investigated. The interaction between IRIP and RS1 was further confirmed in coimmunoprecipitation assays. The transporter regulator RS1 was identified as an IRIP-interacting protein in yeast two-hybrid screening. Besides ischemia/reperfusion, endotoxemia also activated the expression of IRIP in the liver, lung, and spleen. Mouse IRIP mRNA was expressed in all tissues tested, the highest level being in the testis, secretory, and endocrine organs. IRIP cDNA was isolated in a differential display analysis of an ischemia/reperfusion-treated kidney RNA sample. We report the identification and characterization of a new ischemia/reperfusion-inducible protein (IRIP), which belongs to the SUA5/YrdC/YciO protein family.
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