Serial micropuncture analysis of glomerular function in two rat models of glomerular sclerosis.

Abstract

We have recently developed a micropuncture technique to assess repeatedly function of the same nephrons in chronic renal disease and subsequently examine the morphology of their glomeruli by serial thin-section histological analysis. Using this approach, a potential causal linkage between early functional patterns and late structural abnormalities was examined in glomeruli of two established rat models of glomerular sclerosis. The models are (a) puromycin aminonucleoside (PAN) administration in unilaterally nephrectomized Munich-Wistar rats and (b) adriamycin (ADM) treatment in nonnephrectomized Munich-Wistar rats. Single nephron GFR (SNGFR) and glomerular capillary hydraulic pressure (PGc) were measured repeatedly for 8 (PAN rats) or 31 wk (ADM rats). In all animals studied, values for PGC remained at, or slightly below, levels measured before PAN or ADM administration. SNGFR values declined progressively in all glomeruli in PAN rats. Although some glomeruli in ADM rats had an increase in SNGFR above levels observed in nonnephrectomized control rats, these hyperfiltering glomeruli did not have abnormally high PGC nor did they exhibit glomerular sclerosis at the completion of the study. Histological analysis revealed the existence of a significant inverse correlation between the degree of sclerosis and SNGFR assessed at the time of sacrifice in both PAN and ADM groups. Chronic administration of captopril, an angiotensin I converting enzyme inhibitor, in PAN rats substantially attenuated development of glomerular sclerosis without affecting PGC in earlier stages. The observations in these models indicate that glomerular hyperfiltration and hypertension are not required for the development of glomerular sclerosis in renal diseases, and angiotensin I converting enzyme inhibitor can exert its protective effect independently of its effect on glomerular capillary pressure.

Immunomorphometric Studies of Proteinuria in Individual Deep and Superficial Nephrons of Rats

“…The pathological changes in each of the models were qualitatively similar to those previously described in these models and included focal thickening of glomerular and tubular basement membranes and of Bowman's capsules, as well as focal expansions of the glomerular mesangial matrix and early segmental glomerulosclerosis, focal tubular dilatation, and casts and interstitial fibrosis (Bolton et al, 1976;Couser and Stilmant, 1975;Elema and Arends, 1975;Feld et al, 1977;Fogo et al, 1988;Yoshioka et al, 1988). In general, these changes were more severe in the older rats of each group.…”

“…Although heterogeneity of structure and function among nephrons has been documented, the precise relationship of proteinuria to structural change in individual nephrons in these models has not been clearly established. Experimental evidence concerning heterogeneity of glomerular function among nephrons in several rat models has been largely derived from studies of the superficial nephrons that are accessible to micropuncture analysis (Allison et al, 1974;Fogo et al, 1988;Ichikawa et al, 1982;Lewy and Pesce, 1973;Yoshioka et al, 1988). However, analysis of deeper nephrons is only inferential, because they are not accessible for micropuncture.…”

Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury

“…Adriamycin causes well-described podocyte injury in rats (21), but its nephrotoxicity in mice is strain dependent. Balb/C mice are susceptible to podocyte injury by Adriamycin (22,23), whereas other strains that have been tested normally are resistant (24). We determined that preexisting expression of podocyte COX-2 in a mouse strain (B6/D2) that otherwise is resistant to Adriamycin injury sensitized the podocytes to injury, indicated by foot process effacement and albuminuria.…”

Mechanisms and Treatment of CKD

“…12 Mechanical strain may also increase angiotensin II (AngII) production and the expression of angiotensin type 1 receptors in podocytes, 13 and AngII may directly impair the glomerular barrier sieving function-possibly through inhibited nephrin expressionindependent of its hemodynamic effects. 14 Moreover, disruption of glomerular permselectivity with eventual proteinuria and progressive glomerulosclerosis is observed in experimental models that are characterized by normal capillary glomerular pressure, such as adriamycin or puromycin nephrosis 15 and aging-associated glomerulosclerosis in male Munich-Wistar rats. 16 Thus, impaired glomerular sieving appears to initiate and perpetuate parenchymal damage, and ultimately renal scarring and insufficiency, through a common pathway that, independent of capillary pressure, results in increased protein content of the glomerular filtrate with protein overload to glomerular and tubular epithelial cells (Figure 1).…”