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Glucocorticoid activates glomerular antioxidant enzymes and protects glomeruli from oxidant injuries
T Kawamura1, T Yoshioka, T Bills
1Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Abstract:
We examined the effect of glucocorticoid on intrinsic glomerular antioxidant enzyme (AOE) activities. Munich-Wistar rats were treated with daily i.p. injection of vehicle or methylprednisolone [MP, 15 mg/kg body wt, (MP15)] either for three days or nine days. Glomeruli isolated from rats given MP15 had significantly higher activities of total (T-) and manganese (Mn-) superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase than vehicle-treated rats (P less than 0.05). MP15-treated rats were subjected to intrarenal arterial infusion of hydrogen peroxide (35 mumol over 1 hr). Values for urinary protein excretion rate (UprV) after hydrogen peroxide infusion were markedly lower in rats pretreated with MP15 for both three days and nine days than in untreated rats (109 +/- 18 and 55 +/- 24 vs. 416 +/- 73 micrograms/min, respectively, both P less than 0.005). To test whether the same therapeutic intervention attenuates reactive oxygen species (ROS)-mediated glomerular injury in another model, rats given a single i.v. dose of puromycin aminonucleoside (PAN) (50 mg/kg body wt) were treated with daily i.p. injection of vehicle or MP15. Two days after PAN administration, when compared to vehicle-treated controls, PAN rats given MP15 had significantly higher activities of Mn-SOD, GSH-Px and catalase. After eight days of PAN injection, T- and Mn-SOD activities were, likewise, significantly higher in MP15- than vehicle-treated PAN rats. PAN rats given MP15 also had substantially less proteinuria, compared to PAN rats given vehicle alone, UprV averaging 32.3 +/- 9.4 versus 159.0 +/- 13.8 mg/24 hr (P less than 0.05). Elevated glomerular malondialdehyde (MDA) level characteristic of PAN rats was absent in rats treated with MP15. Moreover, epithelial foot process fusion and cell vacuolization seen in vehicle-treated PAN rats were markedly attenuated in MP15-treated PAN rats. These data indicate that the mechanism for therapeutic effect of glucocorticoids on ROS-mediated renal injuries includes an enhancement of endogenous glomerular AOE activities, which attenuates lipid peroxidation of glomerular tissue.
Insights
Glucocorticoids, like methylprednisolone, boost antioxidant enzyme activities in rat kidneys, protecting against reactive oxygen species-mediated injury and reducing proteinuria.
Area of Science:
- Nephrology
- Biochemistry
- Pharmacology
Background:
- Glucocorticoids are widely used to treat various kidney diseases.
- Reactive oxygen species (ROS) play a significant role in the pathogenesis of glomerular injury.
- The effect of glucocorticoids on intrinsic glomerular antioxidant enzyme (AOE) activities remains to be fully elucidated.
Purpose of the Study:
- To investigate the impact of methylprednisolone (MP) on glomerular antioxidant enzyme activities.
- To determine if MP treatment attenuates reactive oxygen species (ROS)-mediated glomerular injury in rat models.
Main Methods:
- Munich-Wistar rats were treated with methylprednisolone (MP15) or vehicle.
- Glomerular antioxidant enzyme activities (SOD, GSH-Px, catalase) were measured.
- Rats were subjected to hydrogen peroxide infusion or puromycin aminonucleoside (PAN) administration to induce kidney injury.
- Urinary protein excretion and glomerular malondialdehyde (MDA) levels were assessed.
Main Results:
- MP treatment significantly increased glomerular activities of total SOD, Mn-SOD, GSH-Px, and catalase.
- MP pretreatment markedly reduced urinary protein excretion following hydrogen peroxide infusion.
- In the PAN-induced nephropathy model, MP treatment increased antioxidant enzyme activities and significantly reduced proteinuria.
- MP treatment attenuated glomerular histological damage and reduced lipid peroxidation (MDA levels) in PAN-treated rats.
Conclusions:
- Glucocorticoid therapy, exemplified by methylprednisolone, enhances endogenous glomerular antioxidant enzyme activities.
- This enhancement of AOE activities is a key mechanism by which glucocorticoids exert therapeutic effects in ROS-mediated renal injuries.
- Glucocorticoids attenuate lipid peroxidation and protect glomerular structures from oxidative damage.