GLOMERULAR LESIONS IN NON-OBESE DIABETIC MICE

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NOD mice spontaneously develop insulin-dependent diabetes mellitus (IDDM) secondary to immunologically-mediated beta cell destruction in pancreatic islets. These mice exhibit an increase in the amount of mesangial matrix before diabetes mellitus occurs and are therefore "prone to glomerulosclerosis". Shortly after the appearance of diabetes, there is an accentuation of the renal lesions consisting of mesangial sclerosis, thickening of glomerular basement membranes, and albuminuria. Morphometric analysis showed that the kidney weight and glomerular size were increased in diabetic mice, compared to non-diabetic mice, and that the ratio glomerular volume/kidney weight was elevated in diabetic mice. We explored by competitive PCR of isolated glomeruli the glomerular turnover of the extracellular matrix components. Prior to the appearance of diabetes the levels of type IV collagen mRNA were 3-4 times higher than in SJL mice who have normal glomeruli. In addition the NOD mice had fewer glomeruli than the SJL and those were larger. Therefore the NOD strain has a propensity to develop sclerosis irrespective of diabetes which is underlain by an abnormal level of expression of basement membrane gene expression and by a reduced number of glomeruli. Shortly after the occurrence of diabetes mellitus we found an upregulation of laminin but not collagen gene expression. This was associated with an increase in TGF-beta1 gene expression which may represent one of the early molecular events in diabetic nephropathy. We also found that there was accumulation of the advanced glycosylation end products in the kidneys shortly after the onset of diabetes.