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 hyperglycemia on renal structure and function using a model of non-insulin-dependent 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 with the development of definitive age-dependent renal structural changes. These changes consisted of thickening of glomerular basement membrane at 35 weeks and tubular basement membrane. This thickening was accompanied by marked glomerular hypertrophy resulting from a parallel increase in total capillary luminal volume and mesangial volume, but fractional capillary and mesangial volumes remained unchanged. There was evidence of podocyte injury, as assessed by de novo expression of desmin. In contrast, there was no evidence 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 macrophage infiltration was elevated significantly in 35-week GK rats. The structural changes described in the GK rat are similar to those described in prolonged non-insulin-dependent diabetes mellitus patients who have not developed overt renal disease. This model allows us to investigate further the mechanisms involved in the pathogenesis of the consequences of prolonged hyperglycemia.
Phillips
A O
AO
Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, Wales. PhillipsAO@cf.ac.uk
Baboolal
K
K
Riley
S
S
Gröne
H
H
Janssen
U
U
Steadman
R
R
Williams
J
J
Floege
J
J
D000375:Aging; D000818:Animals; D001485:Basement Membrane / Q000473:pathology*; D003893:Desmin / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D006984:Hypertrophy; D007668:Kidney / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology* / Q000648:ultrastructure; D008264:Macrophages; D008297:Male; D008854:Microscopy, Electron; D009000:Monocytes; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar
D003893:Desmin