CELL APOPTOSIS AND PROLIFERATION IN EXPERIMENTAL CHRONIC OBSTRUCTIVE UROPATHY

Cell proliferation and apoptosis in kidneys with chronic obstructive u ropathy (COU) have not been adequately studied. Whether these fundamen tal cellular processes play any role in the pathogenesis and evolution of COU remains undetermined. Sprague-Dawley rats with COU induced by unilateral ureteral ligation were sacrificed at postoperative days 1, 6, 9, 15, 25, 34, 43, 60, 75, and 90, and were compared with control, sham-operated rats sacrificed at days 0, 15, 43, and 90. The kidneys w ith ureteral ligation, the contralateral kidneys, and the control kidn eys were submitted to in situ end-labeling of fragmented DNAs for the detection of apoptotic cells, and to immunostaining with many monoclon al antibodies directed against the nuclear antigens associated with ce ll proliferation for the detection of proliferating cells. Additional rats with COU were also submitted to BrdU labeling to detect prolifera ting cells. The tubular, interstitial, and glomerular cells showing ei ther apoptosis or proliferation were separately quantitated and the ob tained data were correlated with dry kidney weight, tubular diameter, glomerular surface area and interstitial volume. Apoptotic tubular cel ls in kidney with COU increased rapidly, reaching 30-fold that of cont rol at day 25, which was followed by an equally rapid decrease to the control level. During the same period, both the dry kidney weight and the mean tubular diameter decreased markedly. These data suggest that apoptosis may play a significant role in tubular atrophy and renal wei ght loss. The rapid increase in tubular cell apoptosis was immediately preceded by a 37% gain in the dry kidney weight over the control; jus t before that increase, there was also an approximate 60-fold increase in the proliferation rate of tubular cells detected by immunostaining for proliferating nuclear antigen or by BrdU labeling. The significan ce of this intriguing temporal relationship of tubular cell apoptosis and proliferation remains to be elucidated, but it may have pathogenet ic implications. In contrast to the rise and fall of the frequency of tubular cell apoptosis and proliferation, the frequency of interstitia l cell apoptosis and proliferation displayed continuous increase rewar d the end of the experiment, with a roughly parallel increase in the i nterstitial damage. Apoptosis and proliferation of glomerular cells in kidneys with COU did not show any significant changes throughout the experiment. In conclusion, the obtained data suggest that tubular cell apoptosis may be pathogenetically related to the tubular atrophy and renal tissue loss in COU, and that proliferation and apoptosis of inte rstitial cells may play a role in the observed interstitial changes in this model. This study should provide the impetus for further explora tion of the mechanisms of cell death and cell proliferation as a novel venue for understanding the pathogenesis of COU.