Progression after release of obstructive nephropathy

Abstract

Progressive glomerular and tubulointerstitial fibrosis develop in 1-year-old rats even after relief (R) of unilateral ureteral obstruction (UUO) at 5 days of age. The present study investigated whether a progressive renal injury model of UUO could be achieved after reversal of UUO (RUUO) in adult instead of neonatal rats. The potential for alpha-tocopherol modulation of mRNA for the fibrogenic cytokine, transforming growth factor-beta1 (TGFbeta1), apoptosis (TUNEL assay), and the presence of the stress protein, heat shock protein-70 (HSP-70), was also studied in this post-obstructive model. Male Sprague-Dawley rats weighing 125-150 g were randomly assigned to groups of 4 animals each for durations of 7 or 14 days of alpha-tocopherol supplementation after RUUO. The groups included: (i) sham, regular chow; (ii) RUUO, regular chow; (iii) RUUO, contralateral nephrectomy (NX); and (iv) RUUO, NX plus alpha-tocopherol supplementation. We found a significant increase in the ratio of kidney weight/body weight in the RUUO+NX group at 14 days compared with the sham and RUUO groups. This rise in the RUUO+NX group was significantly reduced after 14 days of alpha-tocopherol administration. The elevated level of kidney TGFbeta1 mRNA in the RUUO+NX group was only partially reduced at 7 days. But at 14 days this became significantly reduced with the continued alpha-tocopherol treatment. The HSP-70 staining and the apoptosis of the kidney showed results parallel to those of TGFbeta mRNA at 14 days. To separate the effects of hypertrophy after unilateral NX from the RUUO studies, we carried out a second experiment in control animals subjected to NX, with and without alpha-tocopherol supplementation. Fourteen days after NX, the apoptosis and TGFbeta1 mRNA showed no significant differences from the control animals. Our data suggest that a model of progressive renal injury in RUUO can be established in adult rats. After contralateral NX, the progressive injury is evidenced by the increase in the ratio of kidney weight/total body weight, the apoptotic counts, as well as fibrogenic cytokine TGFbeta1 mRNA in the post-obstructed kidney. Finally, our data also support the concept that alpha-tocopherol is renal protective, as judged by TGFbeta1 mRNA, apoptosis, and HSP-70 staining, even in the progressive disease process of the post-obstructed model.