A role for reactive oxygen species in the pathogenesis of focal glomerulosclerosis

Abstract

Previous studies have indicated that reactive oxygen species play a key role in puromycin aminonucleoside (PAN)-induced proteinuria in the acute nephrotic phase, and glomerular infiltration of macrophages (M phi) in the acute phase has a critical impact on the subsequent progression to glomerular sclerosis. In the present study, we examined the effect of deferoxamine (DFO), which is known to inhibit the generation of hydroxyl radical on the proteinuria, renal function and morphological changes in PAN-induced chronic glomerulopathy. Rats given a single dose of PAN (150 mg/kg BW, i.p.) were not treated (Group 1, n = 12) or treated with DFO (Group 2 and 3). In Group 2 rats (n = 12), 30 mg of DFO was given for 12 weeks after PAN injection (every day for the first 2 weeks, 3 times a week for the following 2 weeks, once a week for the last 8 weeks). In Group 3 rats (n = 14), DFO was given in an identical manner with Group 2 until 2nd week and was discontinued thereafter. 24-hour urinary protein excretion (UprV) was measured at 1st, 2nd, 4th, 8th, 12th, and 24th weeks. The percentage of segmentally sclerosed glomeruli (%SS), creatinine clearance (Ccr), and serum malondialdehyde levels (MDA) were determined at the 24th week. The average number of M phi per glomerulus (# M phi) was determined at the 4th, 8th and 24th weeks after PAN injection, by biopsy and autopsy. Compared to Group 1 rats, Group 2 rats had a significantly lower amount of UprV throughout the period with marked attenuation in %SS and Ccr. In contrast, UprV in Group 3 was comparable to that in Group 1 except for the 2nd week, and there was no significant difference in %SS or Ccr between Group 1 and 3. Of note, # M phi at 4th week, which significantly correlated with %SS, substantially decreased in Group 2 compared to Group 1 or Group 3 (p < 0.05). These data suggest that the oxidant stress persisting from the acute to the chronic phase of PAN nephropathy plays an important role in inducing glomerular sclerosis. The prevention of progressive glomerular sclerosis following DFO therapy might be associated with an improvement in early glomerular in filtration of M phi.