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Kidney International (1980) 17, 338–349
Enhanced recovery from acute renal failure by the postischemic infusion of adenine nucleotides and magnesium chloride in rats
Norman J Siegel1, Wayne B Glazier1, Irshad H Chaudry1, Karen M Gaudio1, Bernard Lytton1, Arthur E Baue1 and Michael Kashgarian1
Enhanced recovery from acute renal failure by the postischemic infusion of adenine nucleotides and magnesium chloride in rats. Although a number of manipulations prior to or during the initiation phase of an acute renal injury will modify the degree of functional impairment, agents administered after the acute insult usually have been ineffective. In the present study, adenine nucleotides (AMP, ADP, or ATP) combined with magnesium chloride were infused after an ischemic renal injury. Twenty-four hours later: (1) rats that received no infusion or one of the components of the mixture alone had reduced CIn (355 40 l/min/100 g of body wt vs. 977 40 control value), decreased RBF (3550 205 l/min/100 g of body wt vs. 5095 171 control value), elevated FENa (0.65 0.10% vs. 0.17 0.04 control value), and diminished UOsm (862 110 mOsm/kg vs. 1425 132 control value); (2) rats given dopamine or phenoxybenzamine maintained low CIn (365 50) despite improved RBF (4678 222); (3) rats infused with either AMP, ADP, or ATP combined with magnesium chloride had markedly improved CIn (594 44, P < 0.01), increased RBF (4269 223, P <0.01), normalized FENa (0.18 0.07%, P < 0.01), and improved UOsm (1201 106 mOsm/kg, P < 0.05). In animals given no infusion or only magnesium chloride, ultrastructural studies demonstrated focal cellular necrosis and marked generalized tubular cell and mitochondrial swelling, whereas rats infused with ATP and magnesium chloride had fewer ultrastructural changes with better preservation of cellular morphology. Rats treated with ATP and magnesium chloride had improved CIn despite ischemic periods of 30, 45, and 60 min; and the degree of improvement was directly related to the quantity of ATP and magnesium chloride administered. The cellular content of exogenously administered ATP was 2.5 times greater in previously ischemic kidneys than in nonischemic kidneys. The data indicate that adenine nucleotides combined with magnesium chloride when infused after the initiation of acute renal failure significantly improve both CIn and tubular function and suggest that these agents effectively enhance recovery following an ischemic renal insult.
J Biol Chem. 2003 Nov 28;278 (48)
The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death.
Young-Woo Seo, Jin Na Shin, Kang Hee Ko, Jong Hee Cha, Jae Yoon Park, Byoung Rai Lee, Cheol-Won Yun, Young Myeong Kim, Dai-wu Seol, Dong-wook Kim, Xiao-Ming Yin, Tae-Hyoung Kim
Department of Biochemistry, Chosun University School of Medicine, Dong-Gu, Gwangju 501-759, Korea.
Genotoxic stresses stabilize the p53 tumor suppressor protein which, in turn, transactivates target genes to cause apoptosis. Although Noxa, a "BH3-only" member of the Bcl-2 family, was shown to be a target of p53-mediated transactivation and to function as a mediator of p53-dependent apoptosis through mitochondrial dysfunction, the molecular mechanism by which Noxa causes mitochondrial dysfunction is largely unknown. Here we show that two domains (BH3 domain and mitochondrial targeting domain) in Noxa are essential for the release of cytochrome c from mitochondria. Noxa-induced cytochrome c release is inhibited by permeability transition pore inhibitors such as CsA or MgCl2, and Noxa induces an ultra-structural change of mitochondria yielding "swollen" mitochondria that are unlike changes induced by tBid. This indicates that Noxa may activate the permeability transition-related pore to release cytochrome c from mitochondria into cytosol. Moreover, Bak-oligomerization, which is an essential event for tBid-induced cytochrome c release in the extrinsic death signaling pathway, is not associated with Noxa-induced cytochrome c release. This finding suggests that the pathway of Noxa-induced mitochondrial dysfunction is distinct from the one of tBid-induced mitochondrial dysfunction. Thus, we propose that there are at least two different pathways of mitochondrial dysfunction; one mediated through Noxa in response to genotoxic stresses and the other through tBid in response to death ligands.