Abstract 135: Alubuminuria Causes Disorder of Cytochrome P450 Metabolism of Arachidonic Acid in the Kidney of Nephrotic Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Yoshikazu Muroya ◽  
Osamu Ito ◽  
Rong Rong ◽  
Yoshiko Sakata ◽  
Kenta Takashima ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Western Blot ◽  
Protein Level ◽  
Cell Damage ◽  
Sprague Dawley ◽  
Renal Circulation ◽  
Puromycin Aminonucleoside ◽  
Tubulointerstitial Damage ◽  
Cyp Metabolism

Alubuminuria is an aggravating factor for chronic kidney disease. Fatty acids bound to albumin are overloaded to the proximal tubules in alubuminuria and contribute to tubulointerstitial damage. It is known not only the β-oxidation ability but the ability of cytochrome P450 (CYP) metabolism of arachidonic acid (AA) is high in the kidney. Epoxyeicosatrienoic acids synthesized primarily by CYP2C and 20-hydroxyeicosatetraenoic acid synthesized by CYP4A affect tubular function and renal circulation. However, it isn’t clear CYP metabolism of AA would change in alubuminuria. The study tested changes of CYP metabolism of AA in the kidney of nephrotic rats. Sprague-Dawley rat (SD) and Nagase Analbuminemic rat (NAR) with inherited hypoalbuminemia were used and nephrotic syndrome was induced by Puromycin Aminonucleoside (PAN; 100 mg/kg, iv). Rats were randomly divided into four groups; (1) SD group; (2) SD treated with PAN group (PAN group); (3) NAR group; (4)NAR treated with PAN group (NAR+PAN group). Rats were killed on the 14th day and urinary 8OHdG, a marker of oxidative stress in the kidney, and urinary NAG, a marker of proximal tubular cell damage, were measured. The protein level of enzymes in the kidney was analyzed by Western blot and immunohistochemistry. Compared with the SD group, albuminuria, 8OHdG and NAG increased respectively to 847%, 154% and 903% in the PAN group, and Western blot showed the protein levels of CYP2C23 and CYP4A decreased to 45% and 49% without change of the protein level of PPARα, a nuclear receptor regulating fatty acid metabolism, in the PAN group. Immunohistochemistry showed the localization of CYP2C23 and CYP4A in the proximal tubule and confirmed the results by Western blot. Otherwise, we could find no difference in albuminuria, tubulointerstitial damage and the protein level of CYP2C23 between the NAR group and the NAR+PAN group. Compared with the NAR group, the protein level of CYP4A decreased to 68% in the NAR+PAN group. Alubuminuria caused tubulointerstitial damage and decreased the expressions of CYP2C23 and CYP4A in the nephrotic kidney. This study suggested the disorder of CYP metabolism of AA would affect renal circulation in alubuminuria and CYP4A would be affected by anything except alubuminuria in PAN rats.

Disorder of fatty acid metabolism in the kidney of PAN-induced nephrotic rats

2012 ◽  
Vol 303 (7) ◽  
pp. F1070-F1079 ◽  
Author(s):  
Yoshikazu Muroya ◽  
Osamu Ito ◽  
Rong Rong ◽  
Kenta Takashima ◽  
Daisuke Ito ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Lipid Accumulation ◽  
Acid Metabolism ◽  
Kidney Cortex ◽  
Tubular Damage ◽  
Sprague Dawley ◽  
Puromycin Aminonucleoside ◽  
Fatty Acid Binding ◽  
Tubulointerstitial Damage

Proteinuria is considered to play an essential role in the progression of tubulointerstitial damage, which causes end-stage renal disease. Fatty acid-binding albumins are filtered through glomeruli and reabsorbed into proximal tubular epithelial cells (PTECs). However, the role of fatty acid metabolism associated with albuminuria in the development of tubulointerstitial damage remains unclear. Thus, the present study was designed to determine the changes of fatty acid metabolism in the nephrotic kidney. To induce nephrotic syndrome, Sprague-Dawley rats (SDRs) and Nagase analbuminemic rats (NARs) with inherited hypoalbuminemia were treated with a single injection of puromycin aminonucleoside (PAN). In SDRs, PAN treatment induced massive proteinuria and albuminuria and caused tubular damage, apoptosis, and lipid accumulation in PTECs. Among the enzymes of fatty acid metabolism, expressions of medium-chain acyl-CoA dehydrogenase (MCAD) and cytochrome P-450 (CYP)4A significantly decreased in PTECs of PAN-treated SDRs. Expressions of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α and estrogen-related receptor (ERR)α also significantly decreased, without changes in the expression of PPAR-α. In NARs, PAN treatment induced proteinuria but not albuminuria and did not cause tubular damage, apoptosis, or lipid accumulation. Expressions of MCAD, PGC-1α, or ERRα did not change in the kidney cortex of PAN-treated NARs, but the expression of CYP4A significantly decreased. These results indicate that massive albuminuria causes tubular damage and lipid accumulation with the reduction of MCAD, CYP4A, PGC-1α, and ERRα in PTECs.

scholarly journals Arachidonic Acid Metabolism and Kidney Inflammation

2019 ◽  
Vol 20 (15) ◽  
pp. 3683 ◽  
Author(s):  
Tianqi Wang ◽  
Xianjun Fu ◽  
Qingfa Chen ◽  
Jayanta Kumar Patra ◽  
Dongdong Wang ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Cell Membrane ◽  
Inflammatory Responses ◽  
Membrane Lipids ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Leukotriene B4 ◽  
P450 Monooxygenase ◽  
Wide Range

As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA2 and leukotriene B4 (LTB4) results in inflammatory damage to the kidney. Moreover, the LTB4-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation.

Atypical kinetics of cytochrome P450 2J2: epoxidation of arachidonic acid and reversible inhibition by xenobiotic inhibitors

2021 ◽  
pp. 105889
Author(s):  
Jacqueline Wen Hui Leow ◽  
Ravi Kumar Verma ◽  
Amos Boon Hao Lim ◽  
Hao Fan ◽  
Eric Chun Yong Chan
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Reversible Inhibition ◽  
Kinetics Of

Cytochrome P450 dependent metabolism of arachidonic acid in bovine corneal epithelium

1985 ◽  
Vol 132 (1) ◽  
pp. 343-351 ◽  
Author(s):  
Michal L. Schwartzman ◽  
Nader G. Abraham ◽  
Jaime Masferrer ◽  
Michael W. Dunn ◽  
John C. McGiff
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Corneal Epithelium

Cytochrome P450 Isoform Expression in Human Vascular Endothelial Cells

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 698-698
Author(s):  
Eduardo Barbosa-Sicard ◽  
Eva Kaergel ◽  
Dominik N Muller ◽  
Horst Honeck ◽  
Friedrich C Luft ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Vascular Endothelial Cells ◽  
Arachidonic Acid Metabolism ◽  
Vascular Endothelial ◽  
Rt Pcr ◽  
Pcr Screening ◽  
Mediators Of Inflammation ◽  
Derivatives Of

P29 Epoxy derivatives of arachidonic acid may act as important autocrine and paracrine mediators of endothelial function including regulation of vascular tone and control of inflammation. To identify potential candidates for catalyzing the synthesis of these and further arachidonic acid metabolites, we studied human vascular endothelial cells for the expression of individual cytochrome P450 isoforms belonging to the CYP families 1, 2, 3 and 4. An RT-PCR screening performed with subfamily- and isoform-specific primer pairs revealed mRNAs for the P450 forms 1A1, 1B1, 2C8, 2E1, 2J2, 3A7, 4A11 and 4F2. The identity of the RT-PCR products was confirmed by DNA sequencing. In addition, P450 1A2 mRNA was detected after induction with β-naphthoflavone which also enhanced the expresion of P450s 1A1 and 1B1. P450s 2B6 and 3A4 were not detectable. Similar P450 isoform patterns were obtained analyzing primary human endothelial cells originating from aorta, coronary arteries, dermal microvessels and umbilical veins, as well as an immortalized human endothelial cell line (HMEC-1). Further studies with HMEC-1 cells showed the expression of all human members of the P450 2C subfamily (2C8, 2C9, 2C18 and 2C19). We next used gaschromatography-mass spectrometry to identify the regioisomeric epoxeicosatrienoic acids produced by HMEC-1 cells. Among the P450 forms detected by the RT-PCR screening, P450 2C8 and 2J2 are the leading candidates for producing vasoactive epoxyeicosatrienoic acids. Using recombinant human P450 1A1, we then found that this P450 form catalyzes the formation of various regioisomeric hydroxy derivatives of arachidonic acid. We conclude that P450 1A1 known primarily for its role in polycyclic aromatic hydrocarbon metabolism, may interfere with endothelial arachidonic acid metabolism, particularly after its induction by drugs and xenobiotics. Furthermore, P450s 4A11 and 4F2 probably contribute to the degradation of lipid mediators of inflammation.

The Renal Cytochrome P450 System Generates Novel Arachidonic Acid Metabolites

1989 ◽  
pp. 109-129 ◽  
Author(s):  
Michal Schwartzman ◽  
Mairead A. Carroll ◽  
David Sacerdoti ◽  
Nader G. Abraham ◽  
John C. McGiff
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Cytochrome P450 System ◽  
Arachidonic Acid Metabolites ◽  
Acid Metabolites
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