Experimental Focal Segmental Glomerulosclerosis in Mice

Abstract

Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.

Inhibition of Integrin α2β1 Ameliorates Glomerular Injury

“…We initially defined when the protective effect of loss of integrin a2b1 becomes evident by comparing albuminuria over time in adriamycin-injected control (integrin a2 heterozygotes) and integrin a2KO mice. As previously described, 17 albuminuria significantly increased in adriamycin-injected control mice starting at 1 week, peaked at 2 weeks, and declined at 4 weeks ( Figure 7A). By contrast, albuminuria was reduced, although not statistically different, in adriamycin-injected integrin a2KO mice relative to control mice at 1 week ( Figure 7A).…”

“…To address the function of integrin a2b1 in the glomerular response to injury, we induced glomerular injury in wild-type (WT) and integrin a2-null (a2KO) mice by a single tail vein injection of adriamycin (a model of focal segmental glomerulosclerosis in the BALB/c strain) 3,17 and partial renal ablation (a model that induces hypertension, proteinuria, and glomerulosclerosis in the 129Sv/ev strain). 15 The same types of injures were also performed on integrin a1-null (a1KO) mice, which we showed to be a model of exacerbated glomerulosclerosis after injury.…”

“…Two weeks were chosen, because at this time point, WTmice present high proteinuria and visible glomerular injury. 17 Six to nine mice per treatment were used for this experiment. …”

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.…”

Simvastatin ameliorates glomerulosclerosis in Adriamycin-induced-nephropathy rats

“…Paraffin sections (3 μm) were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS). Glomerulosclerosis was defined as disappearance of cellular elements from the tufts, collapse of the capillary lumen, and folding of the glomerular basement membrane with entrapment of amorphous material [12]. Severity of glomerulosclerosis was evaluated using an index score that included the percent of glomeruli showing sclerosis and the degree of extension of the glomerulosclerosis within the glomeruli, as described previously by Rodriguez et al [13].…”