Expression of apoptosis-related genes and proteins in experimental chronicrenal scarring

Apoptosis has been proposed to play an important role in the progression of renal scarring. The mechanisms that determine whether a cell enters the ap optotic program are complex. Bax and Bel-2 are recognized modulators of thi s event; their relative levels determine the fate of cells. A role for apop tosis in the progression of renal scarring in the remnant kidneys of rats s ubmitted to subtotal nephrectomy (SNx) has been described. This study inves tigated the expression (protein and mRNA) of Bax and Bcl-2 in remnant kidne ys between day 7 and day 120 post-SNx. Northern blot analysis showed that b ax mRNA was increased in remnant kidneys from day 7 (150% of control; P < 0 .05), whereas bcl-2 mRNA was decreased from day 15 (23% of control; P < 0.0 5) resulting in a 14-fold increase in the ratio of bax to bcl-2 mRNA by day 120. Western blot analysis showed similar changes in Bax and Bcl-2 protein in remnant kidneys, resulting in a 147-fold increase in the ratio of Bax t o Bcl-2 on day 120. Immunohistochemistry showed increases in Bax to be loca ted predominantly in tubules in SNx kidneys. Interestingly, Bcl-2 immunosta ining increased in some epithelial cells within atrophic tubules despite th e overall decrease in Bcl-2 protein and mRNA. The overall renal apoptotic c ells correlated closely with the ratio of bax to bcl-2 at both the mRNA and protein levels (r = 0.594 and 0.308, respectively; P < 0.05). Furthermore, tubular apoptosis correlated positively with the mRNA level of bax (r = 0. 471; P < 0.01) and negatively with the mRNA and protein levels of bcl-2 (r = -0.443 and -0.607, respectively; P < 0.01). The increase in the ratio of the death inducer (Bax) to the death repressor (Bcl-2) at the mRNA and prot ein levels may control the apoptosis associated with the progression of tub ular atrophy and chronic renal fibrosis within remnant rat kidneys. These o bservations may have prognostic and therapeutic implications in chronic ren al failure.