Determinants of focal and segmental glomerulosclerosis in the rat after renal ablation:Evidence for involvement of macrophages and lipids

The present study was undertaken to estimate the relative impact of a number of clinicopathologic and glomerular structural changes on severity and composition of focal and segmental glomerular sclerosis (FGS) in rats subjected to renal ablation. Groups of eight 1 1/2-nephrectomized (Nx) and sham-operated (Sh) male Wistar rats were studied at intervals of 2, 4, 8, 12, and 16 weeks. At sacrifice, kidney tissue was embedded in glycolmethacrylate to achieve optimal morphology for light microscopy, immunohistochemistry, and morphometry. FGS lesions were defined by the presence of focal and segmental glomerular scarring and collapse of the glomerular tuft with increased mesangial cellularity (MC), mesangial matrix expansion (MME), and adhesions between the tuft and Bowman's capsule (Adh). The severity of FGS and extent of MC, MME, and Adh was graded seimquantitatively to establish an injury score. The dependence of FGS injury score and of the scores of MC, MME, and Adh on a variety of clinicopathologic and glomerular structural alterations, taking account of possible correlations among them, was estimated with partial correlation and multiple linear regression analysis. The structural parameters included hyalinosis (H, PAS stain), glomerular lipid deposits (GLD, Oil Red O stain), glomerular volume expansion (GVE, morphometry), glomerular cellular proliferation (labeling of S-phase cells by 5 bromo-2'-deoxyuridine, BrdU)-and glomerular influx of macrophages (m-phi), T cells, natural killer cells, and granulocytes (immunohistochemistry with mouse monoclonal antibodies). The clinicopathologic variables were urinary protein excretion (UP), fasting serum cholesterol levels (FChol), body weight (BW), total wet kidney weight (KW), heart weight (HW), and systolic blood pressure (SBP). The best fitting linear regression model, explaining 91% of the total variation of the FGS injury score (multiple r2 = 0.91), included UP as the main clinical, and H as the main structural variable. MC was explained best by BrdU incorporation (multiple r2 = 0.77). The optimal regression model describing MME contained the variables H, mo, and FChol (multiple r2 = 0.84). The extent of Adh formation was optimally described by UP, mo, and FChol (multiple r2 = .88).In conclusion, although none of these statistically significant associations indicate causal relationships, they identify - in addition to UP, H, and cellular proliferation-FChol as a major clinical determinant and glomerular mo influx as a major structural alteration associated with FGS in the setting of renal ablation. The present estimation of the relative impact of each of these factors on the severity of FGS, and on the extent of MC, MME, and Adh individually, may offer a useful framework for further studies concerning pathogenesis and therapeutic modulation of FGS.