DIFFERENTIAL RESPONSE OF GLOMERULAR EPITHELIAL AND MESANGIAL CELLS AFTER SUBTOTAL NEPHRECTOMY

Recent studies in both human and experimental chronic renal disease su ggest that there is a linkage between glomerular hypertrophy and glome rulosclerosis. To further define these relationships, we studied the c hanges in glomerular hypertrophy, procollagen alpha 1(IV) mRNA levels and glomerulosclerosis in rats undergoing 1 2/3 nephrectomy (Nx) or sh am nephrectomy (SNx). Glomerular hypertrophy, measured biochemically b y RNA/DNA and protein/DNA ratios, was significantly increased in Nx co mpared to SNx two days after subtotal renal ablation (RNA/DNA: Nx = 13 3 +/- 8%, SNx = 100 +/- 3% of the mean control value, P < 0.01; protei n/DNA: Nx = 164 +/- 22%, SNx = 100 +/- 10%, P < 0.05) and remained ele vated after 7 and 15 days (RNA/DNA: seven days Nx = 155 +/- 3%, SNx = 100 +/- 13%, P < 0.01; 15 days Nx = 303 +/- 21%, SNx = 100 +/- 24%, P < 0.001; protein/DNA: seven days Nx = 228 +/- 57%, SNx = 100 +/- 18%, P < 0.05; 15 days Nx = 341 +/- 23%, SNx = 100 +/- 18%, P < 0.01). Ligh t microscopic measures of glomerular tuft volume (GTV) were too insens itive to detect glomerular enlargement until 15 days postoperatively, but GTV measured ultrastructurally demonstrated a 20% increment in Nx compared to SNx as early as two days postoperatively (P < 0.01). The l atter increment in GTV was due exclusively to glomerular visceral epit helial cell (GVEC) expansion. Glomerular procollagen alpha 1(IV) mRNA levels were significantly elevated only 15 days after nephrectomy (Nx = 265 +/- 58% of the mean control value, SNx = 100 +/- 12%, P < 0.05; corrected for beta-actin mRNA levels). At this time, exuberant mesangi al expansion measured ultrastructurally contributed to a 1.6 +/- 0.1-f old increase in GTV (P < 10(-5)). and to a relative decrement in the G VEC contribution to glomerular cells plus matrix (P < 0.01). Segmental sclerosis was observed only 15 days postoperatively in Nx (Nx = 1.3 /- 0.4% of glomeruli evaluated, SNx = 0.0%, P < 0.05), and there was a strong correlation between the prevalence of segmental sclerosis and the procollagen alpha 1(IV) mRNA levels in Nx at 15 days (r = 0.93, P < 0.01). There was no significant correlation between the RNA/DNA and protein/ DNA ratios and procollagen alpha 1(IV) mRNA levels. Thus, glo merular regions responded differentially to subtotal nephrectomy. Earl y epithelial cell expansion was followed by later mesangial expansion. Glomerular procollagen alpha 1(IV) mRNA levels were elevated only dur ing the second (mesangial) phase of glomerular hypertrophy, when it co rrelated with glomerulosclerosis, but not during the initial (epitheli al) phase, a pattern consistent with a mesangial origin of the procoll agen alpha 1(IV) mRNA.