Association of prolonged hyperglycemia with glomerular hypertrophy and renal basement membrane thickening in the Goto Kakizaki model of non-insulin-dependent diabetes mellitus

The aim of the current study was to characterize the effects of prolonged h yperglycemia on renal structure and function using a model of non-insulin-d ependent diabetes mellitus: the Goto Kakizaki (GK) rat, which does not have confounding variables, such as hyperlipidemia, obesity, or elevated blood pressure. The data show that hyperglycemia in this model was not associated with the development of significant proteinuria, but it was associated wit h the development of definitive age-dependent renal structural changes. The se changes consisted of thickening of glomerular basement membrane at 35 we eks and tubular basement membrane. This thickening was accompanied by marke d glomerular hypertrophy resulting from a parallel increase in total capill ary luminal volume and mesangial volume, but fractional capillary and mesan gial volumes remained unchanged. There was evidence of podocyte injury, as assessed by de novo expression of desmin. In contrast, there was no evidenc e of mesangial cell activation, as assessed by their de novo expression of alpha -SMA, Interstitial monocyte/macrophage influx increased significantly in GK rats at 12 weeks compared with Wistar controls. Glomerular macrophag e infiltration was elevated significantly in 35-week GK rats. The structura l changes described in the GK rat are similar to those described in prolong ed non-insulin-dependent diabetes mellitus patients who have not developed overt renal disease. This model allows us to investigate further the mechan isms involved in the pathogenesis of the consequences of prolonged hypergly cemia. (C) 2001 by the National Kidney Foundation, Inc.