Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022672 (acute tubular necrosis)
 2,175 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation of fatty acid beta-oxidation (FAO) represents an important mechanism for a sustained balance of energy production/utilization in kidney tissue. To examine the role of stimulated FAO during ischemia, Etomoxir (Eto), clofibrate, and WY-14,643 compounds were given 5 days prior to the induction of ischemia/reperfusion (I/R) injury. Compared with rats administered vehicle, Eto-, clofibrate-, and WY-treated rats had lower blood urea nitrogen and serum creatinines following I/R injury. Histological analysis confirmed a significant amelioration of acute tubular necrosis. I/R injury led to a threefold reduction of mRNA and protein levels of acyl CoA oxidase (AOX) and cytochrome P4A1, as well as twofold inhibition of their enzymatic activities. Eto treatment prevented the reduction of mRNA and protein levels and the inhibition of the enzymatic activities of these two peroxisome proliferator-activated receptor-alpha (PPARalpha) target genes during I/R injury. PPARalpha null mice subjected to I/R injury demonstrated significantly enhanced cortical necrosis and worse kidney function compared with wild-type controls. These results suggest that upregulation of PPARalpha-modulated FAO genes has an important role in the observed cytoprotection during I/R injury.
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PMID:Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. 1075 Dec 29

Previous studies demonstrated that during cisplatin-induced acute renal failure, there is a significant reduction in proximal tubule fatty acid oxidation. We now report on the effects of peroxisome proliferator-activated receptor-alpha (PPAR alpha) ligand Wy-14643 (WY) on the abnormalities of medium chain fatty acid oxidation and pyruvate dehydrogenase complex (PDC) activity in kidney tissue of cisplatin-treated mice. Cisplatin causes a significant reduction in mRNA levels and enzyme activity of mitochondrial medium chain acyl-CoA dehydrogenase (MCAD). PPAR alpha ligand WY ameliorated cisplatin-induced acute renal failure and prevented cisplatin-induced reduction of mRNA levels and enzyme activity of MCAD. In contrast, in cisplatin-treated PPAR alpha null mice, WY did not protect kidney function and did not reverse cisplatin-induced decreased expression of MCAD. Cisplatin inhibited renal PDC activity before the development of acute tubular necrosis, and PDC inhibition was reversed by pretreatment with PPAR alpha agonist WY. Cisplatin also induced increased mRNA and protein levels of pyruvate dehydrogenase kinase-4 (PDK4), and PPAR alpha ligand WY prevented cisplatin-induced increased expression of PDK4 protein levels in wild-type mice. We conclude that PPAR alpha agonists have therapeutic potential for cisplatin-induced acute renal failure. Use of PPAR alpha ligands prevents acute tubular necrosis by ameliorating cisplatin-induced inhibition of two distinct metabolic processes, MCAD-mediated fatty acid oxidation and PDC activity.
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PMID:PPAR alpha ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity. 1461 80

Cisplatin injury to the kidney is characterized, in part, by inhibition of substrate oxidation, inflammation, and tubular cell death in the form of apoptosis and necrosis. Recently, we demonstrated that cisplatin-induced inhibition of substrate oxidation can be reversed by the administration of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands, resulting in amelioration of renal function. We therefore hypothesize that by improving fatty acid oxidation in vivo might protect renal function by reducing both apoptosis and necrosis in cisplatin-treated mice. Mice subjected to a single intraperitoneal injection of cisplatin developed acute renal failure (ARF) at days 3 and 4. At day 4 after cisplatin injection mRNA, protein levels and enzyme activity of proapoptotic renal endonuclease G (Endo G) were increased compared with saline-treated mice. In situ hybridization and immunohistochemical studies localized the increased expression of Endo G mRNA to the cytosolic compartment and Endo G protein to the nuclear compartment of proximal tubules in cisplatin-treated mice. Pretreatment of PPAR-alpha wild-type mice with PPAR-alpha ligand WY-14643 reduced significantly cisplatin-induced increased protein expression and enzyme activity of Endo G and prevented the nuclear translocation of mitochondrial Endo G. Morphological examination of tubular injury in the PPAR-alpha wild-type mice that received PPAR-alpha ligand and cisplatin did show significant amelioration of acute tubular necrosis, as well as a significant reduction in the number of apoptotic cells in the proximal tubule when compared with the cisplatin-treated group. In contrast, in PPAR-alpha-null mice treated with the ligand and cisplatin, Endo G protein expression was not reduced and this was accompanied by lack of protection of kidney function. We conclude that PPAR-alpha ligand protects against cisplatin-induced renal injury via a PPAR-alpha-dependent mechanism by reducing the expression and enzyme activity of proximal tubule Endo G, which results in amelioration of both proximal tubule cell apoptosis and necrosis.
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PMID:PPAR-alpha ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G. 1528 Jan 56