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Cytochrome P-450 as a source of catalytic iron in minimal change nephrotic syndrome in rats
1Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Abstract:
We have recently demonstrated an important pathogenic role for glomerular catalytic iron in the puromycin aminonucleoside (PAN) induced minimal change nephrotic syndrome (MCNS). The source of this iron capable of catalyzing free radical reactions is not known. We examined the role of cytochrome P-450 (CYP) as a source of catalytic iron in a model MCNS induced by single injection of PAN to rats. Treatment of PAN resulted in a marked increase in the catalytic iron associated with significant loss of glomerular CYP content. Administration of CYP inhibitors significantly prevented the injury-induced loss of CYP content and the increase in the catalytic iron in the glomeruli accompanied by a marked decrease in proteinuria. In an in vitro study utilizing glomerular epithelial cells (GEC), CYP inhibitors also markedly prevented the PAN-induced increase in the catalytic iron and hydroxyl radical formation accompanied by significant protection against PAN-induced cytotoxicity. Taken together our data indicate that the CYP, a group of heme protein, may serve as a significant source of this catalytic iron.
Insights
Cytochrome P-450 (CYP) contributes catalytic iron in minimal change nephrotic syndrome (MCNS). Inhibiting CYP reduces iron, free radicals, and proteinuria in this kidney disease model.
Area of Science:
- Nephrology
- Biochemistry
- Toxicology
Background:
- Glomerular catalytic iron plays a pathogenic role in minimal change nephrotic syndrome (MCNS).
- The origin of this iron, which catalyzes free radical reactions, remains unidentified.
- Minimal change nephrotic syndrome is a common cause of nephrotic syndrome in children and adults.
Purpose of the Study:
- To investigate the role of cytochrome P-450 (CYP) as a source of catalytic iron in a rat model of puromycin aminonucleoside (PAN)-induced MCNS.
- To determine if CYP inhibition can mitigate PAN-induced kidney injury.
Main Methods:
- Induction of MCNS in rats using a single injection of PAN.
- Administration of CYP inhibitors to assess their protective effects.
- In vitro studies using glomerular epithelial cells (GEC) exposed to PAN and CYP inhibitors.
- Measurement of glomerular catalytic iron, CYP content, hydroxyl radical formation, and proteinuria.
Main Results:
- PAN treatment significantly increased glomerular catalytic iron and decreased CYP content.
- CYP inhibitors prevented the loss of CYP, the rise in catalytic iron, and reduced proteinuria in vivo.
- In vitro, CYP inhibitors protected GEC from PAN-induced cytotoxicity, catalytic iron increase, and hydroxyl radical formation.
Conclusions:
- Cytochrome P-450 (CYP) heme proteins are a significant source of catalytic iron in the glomeruli.
- CYP contributes to the pathogenesis of PAN-induced MCNS by generating catalytic iron and free radicals.
- CYP inhibition represents a potential therapeutic strategy for MCNS.