Glomerular hemodynamic and structural correlations in long-term experimental diabetic rats.

The glomerular functional and histologic alterations present in rats after 1 year of severe experimental diabetes mellitus were examined. Determination of single nephron function revealed a significant decline (27%) in glomerular plasma flow, primarily as a consequence of a significant increase in afferent arteriolar resistance. Single nephron filtration rate was not decreased proportionate to the decline in glomerular plasma flow, principally because of a significant increase (33%) in the ultrafiltration coefficient. As a result, single nephron filtration fraction was significantly increased by 24%. These functional changes in diabetic rats were similar to those observed after only 1 month of experimental diabetes; however, considerable progression in the glomerular histopathologic characteristics was evident in rats diabetic for 1 year. These changes were characterized by an increased glomerular mesangial matrix, focal glomerulosclerosis, and intense staining for rat IgG and C3 in mesangial regions. We propose that these histologic changes may be a consequence of long-term increases in the filtration fraction particularly associated with decreases in nephron blood flow, functional changes that may favor mesangial localization of phlogogenic macromolecules.

Glomerular permeability to neutral and anionic dextrans in experimental diabetes.

Renal clearances of polydispersed neutral and anionic dextrans were measured in diabetic rats. In addition, urinary protein and albumin excretion rates were determined. Measurements were performed 3 months after the induction of diabetes (i.v. alloxan 50 to 55 mg/kg of body wt) in rats which were either untreated or which received supplemental insulin (6 U of NPH daily) and were compared to those in age-matched SHAM-treated rats. Fractional clearances (relative to inulin) of neutral dextrans remained unchanged in insulin-supplemented rats and were slightly but significantly increased in untreated rats. The application of an isoporous model of the glomerular filtration barrier permitted the conclusion that the size-selective characteristics of the barrier were unaltered in diabetic rats. Fractional clearances of anionic dextrans were significantly reduced 50 to 60% in both diabetic groups suggesting an increase in the negative charge density of the filtration barrier and potentially an increase in restriction to the glomerular filtration of anionic proteins. However, urinary and albumin excretions tended to increase in both groups of diabetic rats, including a 164% increase in albumin excretion in untreated rats. This apparent discrepancy between reduced dextran sulfate clearances and increased protein excretions suggests that factors other than charge-selectivity may be of major importance in determining the filtration of proteins. The marked increase in albumin excretion observed in our diabetic rats appears to be a result of decreased tubular reabsorption rather than increased filtration of albumin.

Determinants of glomerular filtration and plasma flow in experimental diabetic rats.

GFR and, to a lesser extent, RPF are elevated soon after the onset of human diabetes mellitus. The mechanisms involved in these functional changes are unknown. Since the experimental diabetic rat has renal morphological changes similar to those observed in man, we investigated whole-kidney and superficial-nephron glomerular function in this animal model early during the course of the disease. Alloxan-induced diabetes (50 mg/kg BW) is frequently characterized by severe hyperglycemia and retarded body growth. Supplemental insulin administration (6 U of NPH insulin daily) results in normal body growth, although hyperglycemia persists. As a result, we studied four groups of diabetic rats (1) after 1 month of untreated diabetes, (2) after 3 months of untreated diabetes, (3) after 3 months of untreated diabetes followed by 1 month of insulin supplementation, and (4) after 3 months of insulin-supplemented diabetes. After 1 month of untreated diabetes, GFR and SNGFR each declined by 20% compared to age-matched control rats. RPF and SNGFR were both reduced by 33% as a consequence of a 41% increase in RT. Reduced SNGPF together with a 7 mm Hg reduction in PGC caused the fall in GFR and SNGFR. KWs were not significantly different from those of control rats. The functional changes that occurred after 1 month of untreated diabetes did not significantly deteriorate after 3 months of the disease. Insulin supplementation, when instituted for 1 month after 3 months of untreated diabetes, produced no significant improvement in either whole-kidney or superficial-nephron hemodynamics even though body and kidney growth were stimulated. In contrast, insulin supplementation initiated at the onset of diabetes increased both SNGFR and SNGFR to 23% above control values. GFR and RPF each increased in proportion to the 18% increment in kidney size. RT was reduced in these rats, and the pressures that govern glomerular ultrafiltration were not altered from control values. We conclude that in untreated diabetic rats, an increase in RT is the predominant hemodynamic alteration which produces reduced glomerular hemodynamic function. Once established, this defect may not be reversed with 1 month of insulin supplementation. In contrast, small doses of insulin initiated at the onset of diabetes result in renal hypertrophy and proportionate increases in GFR and RPF with a reduction in RT.