Biphasic glomerular hypertrophy in rats administered puromycin aminonucleoside

Abstract

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.

Podocyte Number in Children and Adults

“…Glomerular size increases with normal body growth as well before and during multiple renal pathologies, including both diabetic nephropathy [13][14][15][16][17] and FSGS. [18][19][20][21][22][23][24] It has been suggested that an increase in glomerular size (also known as glomerular hypertrophy) is usually a compensatory mechanism that serves to match physiologic demands and sustain renal function. 25 Over the last decade, our group has described multiple factors associated with compensatory glomerular hypertrophy in humans without overt renal disease, including older age, low nephron number (N glom ), obesity, hypertension, and African-American race.…”

Glomerular Capillary Growth and Cellular Hyperplasia in a Model of Focal and Segmental Glomerulosclerosis

“…In brief, 1 mm slices were embedded in glycolmethacrylate (for stereological estimation of glomerular number, mean glomerular volume and in the present study for estimation of the numerical density of glomerular cells) and randomly sampled 1 mm 3 pieces of cortex were processed for embedding in epon-araldite (for stereological estimation of glomerular capillary length, surface area, and in the present study, number). For full details of these methods see Bertram et al (1992), Bertram (1995) and Cahill et al (1996).…”

“…The first group was previously used in Cahill et al (1996). These rats received injections of either normal saline or puromycin aminonucleoside (2 mg /100 g bodyweight) at weeks 0, 1, 2, 4, 6, 8 and 10.…”

“…Until our previous study (Cahill et al, 1996) this model was not thought to involve glomerular enlargement. However, we found that mean glomerular volume in PAN-treated rats was almost 50% greater than in saline-treated rats at week 7 (Cahill et al, 1996). FSGS had not developed at this time.…”

“…The number of capillary loops per renal corpuscle was estimated in the same rats studied by Cahill et al (1996) using the method of Nyengaard and Marcussen (1993). Then, the contribution of glomerular cell hyperplasia to the glomerular hypertrophy in these rats was determined.…”