Differential response of glomerular epithelial and mesangial cells after subtotal nephrectomy

Abstract

Recent studies in both human and experimental chronic renal disease suggest that there is a linkage between glomerular hypertrophy and glomerulosclerosis. To further define these relationships, we studied the changes in glomerular hypertrophy, procollagen alpha 1(IV) mRNA levels and glomerulosclerosis in rats undergoing 1 2/3 nephrectomy (Nx) or sham nephrectomy (SNx). Glomerular hypertrophy, measured biochemically by RNA/DNA and protein/DNA ratios, was significantly increased in Nx compared to SNx two days after subtotal renal ablation (RNA/DNA: Nx = 133 +/- 8%, SNx = 100 +/- 3% of the mean control value, P < 0.01; protein/DNA: Nx = 164 +/- 22%, SNx = 100 +/- 10%, P < 0.05) and remained elevated 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). Light microscopic measures of glomerular tuft volume (GTV) were too insensitive 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 latter increment in GTV was due exclusively to glomerular visceral epithelial 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). As this time, exuberant mesangial expansion measured ultrastructurally contributed to a 1.6 +/- 0.1-fold increase in GTV (P < 10(-5)), and to a relative decrement in the GVEC 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, glomerular regions responded differentially to subtotal nephrectomy. Early epithelial cell expansion was followed by later mesangial expansion. Glomerular procollagen alpha 1(IV) mRNA levels were elevated only during the second (mesangial) phase of glomerular hypertrophy, when it correlated with glomerulosclerosis, but not during the initial (epithelial) phase, a pattern consistent with a mesangial origin of the procollagen alpha 1(IV) mRNA.

The wt1‐heterozygous mouse; a model to study the development of glomerular sclerosis

“…Although we have shown in this study that wt1/ ‐heterozygosity per se predisposes to the development of glomerular sclerosis, treatment for Wilms' tumour may well accelerate the onset of renal failure. Glomerulosclerosis has been linked to the compensatory hyperfiltration and hypertrophy that ensues following unilateral nephrectomy 29–31. We hypothesize that the glomerular filtration function is impaired in the wt1 het mice at an early stage.…”

PF-03882845, a non-steroidal mineralocorticoid receptor antagonist, prevents renal injury with reduced risk of hyperkalemia in an animal model of nephropathy

“…Concurrent with its effect on UACR, PF-03882845 was more potent than eplerenone in suppressing collagen IV gene and protein expression in kidney cortex. Collagen IV has been associated with glomerulosclerosis in experimental models (Floege et al, 1992; Bergijk et al, 1998; Lee et al, 1998) and humans (Kim et al, 1991; Tamsma et al, 1994; Esposito et al, 1996) with kidney disease. Renal biopsies from patients with diabetic nephropathy indicated a clear increase in α 2 type IV collagen gene and protein in glomeruli compared to controls (Adler et al, 2000).…”

Compensatory Hypertrophy after Partial and Radical Nephrectomy in Adults

“…Contralateral hypertrophy is an important aspect of this situation, although the biological mechanisms that underlie this phenomenon are not well understood. 4,5 Contralateral hypertrophy is impressive in neonates and children, in whom the volume and function of the remaining kidney was documented to almost double. 6,7 In contrast, information on contralateral hypertrophy in adults is much more limited, particularly after PN.…”