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Glomerular dysfunction induced by polymorphonuclear leukocyte-derived reactive oxygen species
1Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2584.
Abstract:
The role of reactive oxygen species (ROS) derived from polymorphonuclear leukocytes (PMN) on glomerular microcirculation was evaluated in Munich-Wistar rats. To induce local activation of PMN, phorbol myristate acetate (PMA, 20 micrograms) was infused unilaterally into the renal artery in six rats and the micropuncture study was performed 18 h later. In these animals, there was a significant (P less than 0.005) glomerular PMN accumulation in the PMA-injected kidney (on average 2.2 +/- 0.2 per 3-microns glomerular section) compared with the contralateral kidneys of the same rats or the vehicle-treated kidneys from a separate group of seven rats (0.2 +/- 0.1 and 0.2 +/- 0.1 per 3-microns glomerular section, respectively). In the PMA-treated kidneys, whole kidney glomerular filtration rate (GFR) was significantly reduced compared with that of the contralateral kidney of the same rats or vehicle-treated kidneys of a separate group of rats (0.61 +/- 0.04, 1.18 +/- 0.05, and 1.02 +/- 0.04 ml/min, respectively, P less than 0.05). This PMA-induced reduction in GFR was largely prevented by pretreatment of rats with a scavenger of hydrogen peroxide, catalase (1,000 kU; n = 7), or by depletion of PMN with an intravenous nitrogen mustard administration (1.7 mg/kg; n = 7). The reduction of GFR in the PMA-treated kidneys therefore appeared to be mediated by the ROS derived from activated PMN. The micropuncture measurement of glomerular microcirculatory dynamics in PMA-treated kidneys without above pretreatment revealed that there was a profound fall in single-nephron GFR and ultrafiltration coefficient and an increase in renal arteriolar resistances (greater in efferent than afferent arteriole).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Reactive oxygen species from activated polymorphonuclear leukocytes significantly reduce glomerular filtration rate. This effect on kidney microcirculation is mediated by ROS and can be prevented by antioxidants or PMN depletion.
Area of Science:
- Nephrology
- Physiology
- Immunology
Background:
- Polymorphonuclear leukocytes (PMN) are key immune cells involved in inflammation.
- Reactive oxygen species (ROS) are byproducts of cellular metabolism with signaling roles.
- The specific impact of PMN-derived ROS on glomerular microcirculation requires further elucidation.
Purpose of the Study:
- To investigate the role of reactive oxygen species (ROS) generated by polymorphonuclear leukocytes (PMN) in modulating glomerular microcirculation.
- To determine the effect of PMN activation on glomerular filtration rate (GFR) and intrarenal hemodynamics.
Main Methods:
- Munich-Wistar rats were used to study glomerular microcirculation.
- Phorbol myristate acetate (PMA) was infused unilaterally into the renal artery to activate local PMN.
- Micropuncture studies were conducted 18 hours post-infusion to assess glomerular PMN accumulation, GFR, and microcirculatory dynamics.
Main Results:
- PMA infusion led to significant glomerular PMN accumulation in the treated kidney.
- A marked reduction in whole kidney and single-nephron GFR was observed in PMA-treated kidneys.
- Pretreatment with catalase (a hydrogen peroxide scavenger) or PMN depletion prevented the GFR reduction.
Conclusions:
- ROS derived from activated PMN play a critical role in reducing glomerular filtration rate.
- Activated PMN significantly impair glomerular microcirculation, leading to decreased GFR and altered intrarenal hemodynamics.
- Targeting PMN-derived ROS may offer a therapeutic strategy for kidney injury involving inflammation.