Biphasic glomerular hypertrophy in rats administered puromycin aminonucleoside

Recent evidence suggests that glomerular hypertrophy is a key event in the development of focal and segmental glomerulosclerosis and hyalinosis (FSGS) in humans and in many experimental models of FSGS. The initial aim of the present study was to determine if glomerular hypertrophy occurs in a puromycin aminonucleoside (PAN) model of FSGS, previously considered not to involve glomerular hypertrophy. Upon identifying significant glomerular hypertrophy, our second aim was to determine the contribution of glomerular capillary growth to this hypertrophy. Female Sprague-Dawley rats (approximately 200 g) were administered either PAN (2 mg/100 g body wt) subcutaneously, or an equivalent volume of 0.9% saline at weeks 0, 1, 2, 4, 6, 8 and 10. Tissue was analyzed at weeks 7 and 13. Unbiased stereological methods were used to estimate a range of glomerular parameters. Mean glomerular tuft volume in PAN-treated rats was 48% greater than in saline-treated rats at seven weeks, and 63% greater at 13 weeks. Similar results were found for mean renal corpuscle volume. FSGS was absent at seven weeks and minor at 13 weeks. Two-way analysis of variance indicated: significant effects (P < 0.05 at least) of PAN on capillary length per glomerulus, capillary surface area per glomerulus, capillary diameter and length of capillaries per unit volume of glomerulus; and significant effects of time on capillary diameter, capillary length per unit volume of glomerulus and capillary surface area per unit volume of glomerulus. The mean length of capillaries per glomerulus was 45% greater in PAN-treated rats at week 7 and 22% greater in PAN-treated rats at week 13. Taken together, these results indicate a biphasic pattern of glomerular hypertrophy in this model. In the first phase (to 7 weeks), an increase in capillary length contributes to glomerular hypertrophy. In the second phase (7 to 13 weeks), the continued glomerular enlargement appears more likely to be due to an increase in capillary diameter and/or mesangial matrix expansion.